Variations in MHC Class II Antigen Processing and Presentation in Health and Disease.

IY34CH10-Neefjes

ARI

V I E W

Review in Advance first posted online on February 22, 2016. (Changes may still occur before final publication online and in print.)

N

I N A

Annu. Rev. Immunol. 2016.34. Downloaded from www.annualreviews.org Access provided by University of Massachusetts - Amherst on 02/24/16. For personal use only.

13:49

C E

S

R

E

11 February 2016

D V A

Variations in MHC Class II Antigen Processing and Presentation in Health and Disease Emil R. Unanue,1 Vito Turk,2 and Jacques Neefjes3,4 1

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110; email: [email protected]

2

Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, SI-1000 Ljubljana, Slovenia; email: [email protected]

3

Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; email: [email protected]

4

Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Annu. Rev. Immunol. 2016. 34:10.1–10.33

Keywords

The Annual Review of Immunology is online at immunol.annualreviews.org

MHC class II, polymorphism, autoimmunity, antigen presentation, cathepsins, inhibitors, processing, HLA

This article’s doi: 10.1146/annurev-immunol-041015-055420 c 2016 by Annual Reviews. Copyright All rights reserved

Abstract MHC class II (MHC-II) molecules are critical in the control of many immune responses. They are also involved in most autoimmune diseases and other pathologies. Here, we describe the biology of MHC-II and MHC-II variations that affect immune responses. We discuss the classic cell biology of MHC-II and various perturbations. Proteolysis is a major process in the biology of MHC-II, and we describe the various components forming and controlling this endosomal proteolytic machinery. This process ultimately determines the MHC-II–presented peptidome, including cryptic peptides, modified peptides, and other peptides that are relevant in autoimmune responses. MHC-II is also variable in expression, glycosylation, and turnover. We illustrate that MHC-II is not only variable in amino acids (polymorphic) but also in its biology, with consequences for both health and disease.

10.1

Changes may still occur before final publication online and in print

IY34CH10-Neefjes

ARI

11 February 2016

13:49

INTRODUCTION


MHC class II (MHC-II) molecules are classical transplantation antigens and the major polymorphic proteins encoded in vertebrate genomes. Their physiological function is to bind peptides and form the macromolecular substrate for T cell recognition (1). Unlike the other class of classical transplantation antigens (MHC class I molecules), MHC-II molecules are expressed only on a select set of immune cells and on epithelial, vascular, and connective tissue cells in response to inflammatory signals (2). CD4+ T cells that interact with MHC-II–bound peptides are a major component of the immune responses to protein antigens (3). CD4+ T cells are the classical helper T cells that, once activated, promote B cell differentiation and antibody production, as well as CD8+ T cell responses. In addition, activated CD4+ T cells secrete many cytokines and chemokines, depending on T helper cell type, which can activate and differentiate other immune cells. Obviously, this step in immune activation must be tightly controlled, as poor or unregulated responses can promote infectious diseases, autoimmune diseases, and cancer. MHC-II alleles are indeed associated with autoimmune diseases; they are often the strongest risk factors (4) and are frequently used as diagnostic criteria. This further illustrates the critical role of MHC-II in the control of immune responses, and this role has clinical consequences. Understanding MHC-II antigen presentation in health and disease may be critical for developing tools to control autoimmune responses and to modulate strong responses against infections and cancer. Here, we describe the general pathway of antigen presentation by MHC-II and then highlight the different steps involved in successful antigen presentation. We emphasize variations of the general scheme that may affect MHC-II–associated immune responses in health and disease.

STRUCTURE AND POLYMORPHISMS OF MHC CLASS II MOLECULES AND THEIR ASSOCIATION WITH DISEASE We now describe the structure of MHC-II molecules, as well as the consequences (in structural terms) of polymorphisms. MHC-II molecules are encoded by the MHC gene locus, which is located on chromosome 6 in humans and chromosome 17 in mice (5). MHC-II is a heterodimer consisting of an α chain and a β chain, which assemble into a structure in which a peptide-binding groove or peptide-binding site is located on top of two immunoglobulin domains. The binding site consists of two α helices on a β-pleated sheet platform, and the peptide sits between the helices (6). The α and β chains are encoded by adjacent genes. The human MHC locus encodes three MHC-II proteins expressed on the cell surface: HLA-DR, HLA-DQ, and HLA-DP. The mouse MHC locus encodes two proteins: I-A and I-E (7). Polymorphic residues are found in the combining site of the β chains of the three human HLA class II molecules. The HLA-DR α chain is invariant, but some degree of polymorphisms exists in the α chains of HLA-DQ and HLA-DP (Figure 1a). Both chains are polymorphic in mouse MHC-II proteins. Projecting the polymorphic amino acids onto the structure of HLA-DR, HLA-DQ, or HLA-DP shows that they are concentrated in and around the peptide-binding groove of these molecules (Figure 1b). Peptides bound to MHC-II usually adopt a stretched polyproline conformation in which some amino acid side chains are solvent exposed and potentially constitute T cell receptor (TCR) contact sites, whereas other side chains, including the MHC anchor residues, point toward the peptide-binding groove (8). Binding of the peptide depends on hydrogen bonding of the peptide backbone with the helices and, importantly, on various chemical interactions between the MHC-II anchor side chains and acceptor sites or pockets in the binding groove. These pockets include the polymorphic MHC-II residues, resulting in different pockets accepting different peptide anchor residues. Consequently, different peptides associate with different MHC-II alleles 10.2

Unanue

· · Turk

Neefjes


IY34CH10-Neefjes

ARI

11 February 2016

13:49

a HLA-DR α

β

HLA-DQ


α

β

HLA-DP α

β

b

HLA-DR1

HLA-DQ

HLA-DP

Figure 1 Polymorphisms in MHC class II (MHC-II) HLA locus products. (a) Location of polymorphic residues in the HLA-DR, HLA-DQ, and HLA-DP molecules. α and β chains are split into α1 , α2 and β1 , β2 domains, shown in light and dark colors, respectively. Sequences are from the European Bioinformatics Institute. Plotted on top is the relative number of polymorphic residues identified at each position of the MHC-II α chains. (b) Polymorphic residues are concentrated in the peptide-binding groove. The MHC-II α chain ( green) and β chain ( gray) form the peptide-binding groove. The position of polymorphic residues is shown in blue for low levels of polymorphism, purple for medium levels, and red for high levels. The peptide in the structures of HLA-DR1, HLA-DQ1, and HLA-DP1 is shown in yellow and contacts most polymorphic residues. Images were made with MAIN software (Turk D. 2013. MAIN software for density averaging, model building, structure refinement and validation. Acta Crystallogr. D 69:1342–57).

(9). The peptides bound to MHC-II molecules have a 9-amino-acid core in the binding groove with flanking residues that vary greatly in length, extending the peptides to approximately 12–16 amino acids. The 9-amino-acid core contains 3–4 MHC-II anchor residues—usually at P1, P4, P6/7, and P9—and the remaining are the exposed, potential TCR contact residues (10). MHC-II differs from MHC-I in that its peptide-binding groove is more open and allows peptides to extend out of the MHC-II structure. MHC-II not only binds long peptides but also interacts with unfolded proteins and even native proteins with segments that possess conformational flexibility (11, 12). These basic facts may relate to the likely evolutionary origin of the MHC peptide-binding groove, which bears some resemblance to the peptide-binding grooves of chaperones (13). Most chaperones also bind unfolded stretches of protein, to prevent their aggregation. MHC molecules may have evolved this mechanism to present the principal unfolded protein structure: a peptide. www.annualreviews.org • MHC-II Presentation


10.3

ARI

11 February 2016

13:49

Peptides have differing features due to polymorphisms that affect their selection by various MHC alleles. As a consequence, segments of a protein will be selected by different MHC alleles, a process that was first named determinant selection. This has repercussions for the control of immune responses. Resistance to infections probably generated evolutionary pressure to select polymorphisms centered around the peptide-binding site. This is probably best exemplified by the rather uneven distribution of MHC alleles in human populations (14, 15). Although several hundred HLA alleles have been identified among the three main MHC-II genes, only a few are present in more than half of the human population. Numerous pathogen attacks during evolutionary history could have shaped an unequal distribution of MHC-I and MHC-II alleles in humans, as well as other vertebrate species. Indeed, some species having limited MHC polymorphisms, such as the Tasmanian devil, are vulnerable to infections and cancer (16). A disadvantage of multiple MHC-II gene expression and of allelic variability is autoimmune responses. For example, self-peptides mimicking microbial proteins might reverse self-tolerance and induce autoimmunity.


IY34CH10-Neefjes

THE SWEET PART OF MHC-II: VARIATIONS AND CONSEQUENCES OF ITS GLYCOPROTEIN NATURE MHC-II molecules are glycoproteins. The MHC-II α chain contains both an N-linked high-mannose carbohydrate chain and a complex-type carbohydrate chain, whereas the β chain contains only an N-linked, complex-type carbohydrate chain. These carbohydrates constitute approximately 12% of the total mass of MHC-II (Figure 2). Complex glycans have considerable volume, but they are mostly flexible and not detected by X-ray crystallography. The α-chain carbohydrate appears to be located at the end of the MHC-II peptide-binding groove, where it moves in a space that is also used by HLA-DM (DM) to interact with MHC-II (17). The carbohydrate chain can swing over the MHC-II peptide-binding groove and may affect the accessibility of the peptide-binding groove to the TCR and antibodies (18). The composition of the N-linked glycans is also variable. Compared with normal cells, many tumor cells have more branched N-linked glycans, which occupy more space (19). By contrast, various viruses (such as influenza) express neuraminidase, which removes the terminal sialic acids of N-linked glycans, reducing their size. Neuraminidase also changes the net negative charge of N-linked glycans (their sialic acid sugars are acidic and negatively charged at neutral pH). These changes in carbohydrate structure may promote access of T cells to the MHC-II molecule, as observed for MHC-I molecules that have one (human) or two (mice) N-linked glycans located immediately around their peptide-binding groove (20). The N-linked sugars of MHC-II are usually ignored, but—given their role in MHC-II structure and size—they probably represent an important and variable modification that modulates MHC-II–restricted responses.

THE GENERAL PATHWAY OF MHC CLASS II ANTIGEN PRESENTATION What is the biological life cycle of MHC-II, and how does it encounter peptides for presentation (Figure 3)? This is a relevant issue, as many, if not most, peptides are derived from self and exogenous antigens that are degraded in late endosomal/lysosomal compartments containing acidic proteases. Like any glycoprotein, MHC-II starts its life in the endoplasmic reticulum (ER). MHC-II is assembled from two glycoproteins, the α and β chains, which—with the help of various ER chaperones—form the MHC-II αβ heterodimer (21). This heterodimer assembles in the ER with a third glycoprotein, the invariant chain (Ii) (21).

10.4

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

Figure 2 An MHC class II (MHC-II) molecule and its carbohydrate cloud. The position of two of the three N-linked glycans of MHC-II (here HLA-DQ1) is indicated in green. The MHC-II α chain ( green) and β chain ( gray) form the peptide-binding groove. Only one or a few of the 11–19 sugars that make a two- to four-branched glycan are resolved in the crystal structure because this part of the sugar chain is restricted in its mobility. The carbohydrate chains move in a space around the MHC-II peptide-binding groove and then limit access to the MHC-II protein part for other proteins such as DM and the TCR of CD4+ T cells. The MHC-II carbohydrates then modulate MHC-II responses. The two gray-green spherical clouds projected on these sites illustrate the area that can be covered by the N-linked glycan. Images were made in MAIN (Turk D. 2013. MAIN software for density averaging, model building, structure refinement and validation. Acta Crystallogr. D 69:1342–57).

Ii can be a homotrimer assembled with up to three MHC-II αβ heterodimers (22). Ii acts as a low-affinity pseudopeptide by filling the peptide-binding groove of MHC-II with a small segment called CLIP (23). This prevents premature binding of other peptides or denatured proteins present in the ER (24). Ii also has a transport function (23, 25). It promotes exit from the ER and sorting of associated MHC-II in the trans-Golgi network (TGN) to a late endosomal acidic compartment called the MHC-II compartment (MIIC) (26, 27). MHC-II–Ii complexes that fail to be sorted at this point arrive at the cell surface. Ii then ensures efficient internalization and transport to the MIIC. Ii contains a critical dileucine sorting motif in its cytoplasmic tail, which targets the complex from the TGN to the MIIC and causes rapid internalization of the MHC-II–Ii complex at the cell surface (28). In the absence of Ii, limited amounts of MHC-II enter the MIIC for peptide acquisition, resulting in impaired immune responses (29, 30). Following entry of MHC-II–Ii complexes into the endosomal route, Ii is stepwise degraded by a series of proteases, including cathepsin S (31) and ultimately SPPL2A (32, 33), which cleaves the transmembrane segment. Trimming of Ii is critical for peptide binding to MHC-II; protease inhibitors such as leupeptin inhibit normal peptide acquisition and even the transport of MHC-II from the MIIC to the plasma membrane (34). Ii is ultimately fully degraded, with the exception

www.annualreviews.org • MHC-II Presentation


10.5

IY34CH10-Neefjes

ARI

11 February 2016

13:49

FcR BCR

Lectin receptor

Plasma membrane

EE TGN +

H

Golgi


H+

MIIC

H+ Autophagosome ER

+

MHC-II

+

Ii pMHC-II

DM

+ MHC-II

DM:DO

pMHC-II

Figure 3 The general pathway of MHC class II (MHC-II) antigen presentation. MHC-II is assembled in the endoplasmic reticulum (ER) and then associates with the invariant chain (Ii). The Ii supports ER exit and the transport of MHC-II to the MHC-II compartment (generally called MIIC), an acidic late endosomal compartment containing proteases and HLA-DM (DM) [and sometimes HLA-DO (DO)]. Antigen can enter the endocytic pathway by fluid phase uptake or with support from receptor proteins. The antigen is degraded, and fragments can be selected for binding to MHC-II and further edited by DM (see inset). DO binds DM and reduces peptide editing. Autophagosomes with a different (often cytosolic/nuclear) protein content can also fuse to the MIIC to deliver cargo for MHC-II antigen presentation. Abbreviations: BCR, B cell receptor; EE, early endosome; FcR, Fc-receptor; PM, plasma membrane; pMHC-II, peptide-loaded MHC-II; TGN, trans-Golgi network.

of a fragment called CLIP, which is protected from proteases when embedded in the MHC-II peptide-binding groove (35). In the MIIC, CLIP is exchanged for proper peptides in a reaction catalyzed by a unique late endosomal chaperone called DM (HLA-DM in humans or H2-DM in mice) (17, 36, 37). The chaperone DM has a structure similar to that of MHC-II but does not bind peptides (38, 39). (This illustrates our previous conjecture that MHC-II molecules may be derived from primitive chaperones.) DM dissociates the CLIP peptide from MHC-II and stabilizes the MHC-II molecule, which now becomes receptive to peptide binding. Of note, CLIP binding affinity varies greatly among different MHC-II allelic variants. Some MHC-II molecules dissociate CLIP rapidly without the involvement of DM (40). Examination of the interactions of DM with HLA-DR1 shows that the DMα chain interacts primarily with the DRα chain near the N terminus of the peptide (17), close to the N-linked glycan. DM causes a conformational change in which a critical tryptophan residue (W43 in the HLA-DRα chain) allows the P1 MHC-II DR binding pocket to 10.6

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

open. This DM-DR complex then favors binding, preferably of high-affinity peptides, which is followed by the release of DM when the DR W43 residue in HLA-DR enters the peptide-binding groove (17). This critical W43 residue is conserved in all MHC-II α chains, indicating the important role of DM in peptide editing throughout the polymorphic MHC-II family. Thus, DM has distinct functions during catalytic peptide acquisition in the MIIC: dissociation of CLIP, stabilization of MHC-II while it exchanges peptides, and, ultimately, peptide editing. As a result, DM edits the peptide repertoire in favor of peptides with higher binding affinities (41, 42). Stable binding of peptides with a low off-rate that persists from several hours to several days is important in the context of the dynamic interactions of antigen-presenting cells (APCs) with T cells (43, 44). In the absence of DM, the peptide repertoire is not optimized, yielding a broader MHC-II–associated peptide repertoire, which includes low-affinity peptides, and reduced positive CD4+ T cell selection (45). Such changes in peptide repertoire are important in the selection of self-peptides in autoimmunity. Of note, MHC-I molecules have to pass what is called the ER quality control system to arrive with proper peptides at the cell surface (46). Whether a similar quality control system sensing MHC-II with optimal peptides exists in endosomes is unknown. The critical factor for peptide presentation is probably time. Within the time period between Ii trimming and cell surface appearance (ranging between 30 minutes and many hours, depending on cell type), peptides are exchanged in the MHC-II peptide-binding groove until a high-affinity complex is achieved. If this process does not take place under optimal conditions, many MHC-II molecules with suboptimal and cryptic peptides may ultimately be presented at the cell surface, possibly with significant consequences (see below). When MHC-II molecules release associated low-affinity peptides at the cell surface, they become receptive to new peptides. If they fail to obtain new peptides, MHC-II molecules may be removed from the cell surface for degradation. It is possible that recycling DM molecules [they have a tyrosine-based internalization motif (47)] recognize peptide-empty MHC-II molecules and return them to the MIIC, where they can be loaded with new peptides or where they are degraded along with most endocytosed proteins. These then yield new peptides for MHC-II. Many MHC-II–derived peptides are indeed found in the MHC-II–associated peptidome. The cell surface half-life of MHC-II is also controlled and depends on cell type and differentiation state. MHC-II in immature dendritic cells (DCs) has a half-life of approximately 6 hours; its half-life increases to days in mature DCs (43, 44). The increased turnover of MHC-II in immature DCs is attributed to the transmembrane E3 ligase MARCH1, which ubiquitinates the cytoplasmic tail of the MHC-II β chain (48, 49) [a system also used by some herpes viruses and Salmonella to prevent presentation by MHC molecules (50, 51)]. MHC-II is then internalized and sorted for degradation within late endosomal multivesicular bodies (MVBs). The surface half-life of MHC-II in mature DCs is considerably extended because these cells have limited endocytosis, but also because MARCH1 expression is downregulated. This allows activated DCs to present relevant antigens for a long period of time. MARCH1 is also critical for MHC-II expression in B cells (52) and may be downregulated when B cells differentiate into B cell blasts, increasing the half-life of surface MHC-II. Finally, MARCH1 appears to prevent recycling of cell surface MHC-II molecules through early endosomes, instead promoting MHC-II degradation in the late endosomes of activated DCs (53). Ubiquitinated transmembrane proteins (including MHC-II) are substrates of the ESCRT (endosomal sorting complexes required for transport) machinery, which targets these structures for lysosomal destruction (54). Whether a similar system is activated when monocytes differentiate into macrophages or when B cells differentiate into B cell blasts is unclear. The cell biology of MHC-II is understood in great detail (Figure 3), although many variations on the general pathway outlined above exist. These variations may have serious consequences for www.annualreviews.org • MHC-II Presentation


10.7

ARI

11 February 2016

13:49

the MHC-II associated peptidome and—as a result—for health and disease. Much of this variation occurs in the MIIC. For a better understanding of antigen presentation by MHC-II molecules, the site where MHC-II acquires antigenic peptides should be properly identified. The identification of this site created considerable confusion in the early 1990s, as illustrated by the different names given to it. Its original names included CIIV [class II vesicles (55)], MIIC [MHC-II compartment (27)], and others, all representing different structures. To define the relevant site in the endosomal pathway, the minimal system required for antigen presentation should be considered (56). In general, MHC-II antigen presentation requires acidic compartments, as antigen presentation can be inhibited by ammonium chloride or chloroquine, which neutralizes the acidic pH required for optimal activity of most endosomal proteases (57). Obviously, MHC-II and the chaperone DM should be present. Because MHC-II molecules are endocytosed when associated with Ii, and because DM is recycled between late endosomes and the plasma membrane, these molecules transiently pass through earlier compartments and are usually difficult to detect in them (58). In addition, because early endosomes are not highly acidic and have low concentrations of proteases to digest antigens, and because lysosomes are considered end-stage compartments, late endosomal compartment(s) are the most obvious sites at which all constituents for efficient MHC-II antigen processing and acquisition meet. Visualized with electron microscopy, these structures resemble multilamellar structures and/or multivesicular structures containing late endosomal markers, such as CD63, CD81, LAMP1, and others, as in the original description of the MIIC (27) (Figure 4). MVBs are generated by the ESCRT system, which induces the formation of internal lysosomal vesicles (ILVs) within a limiting membrane. In general, proteins are sorted from the limiting membrane into ILVs after ubiquitination of their cytoplasmic tails (59). MHC-II and DM can be ubiquitinated and become concentrated on the surface of ILVs (60), where they interact with


IY34CH10-Neefjes

33nm Figure 4 Two architectures of the MHC class II (MHC-II) compartment. Electron micrograph of a section of activated human monocyte–derived dendritic cells (DCs). The section is stained for MHC-II (visualized by gold particles and seen here as dense dots). MHC-II primarily resides on internal vesicles. The two structures are called multilamellar (left) and multivesicular (right). Because the limiting membrane ultimately fuses to the plasma membrane, MHC-II has to find a way back to the limiting membrane of the two structures. Alternatively, MHC-II is secreted in the form of exosomes.

10.8

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

tetraspanin proteins such as CD63, CD9, CD81, and CD82 (61). These tetraspanin proteins form protein-based webs in the lipid bilayer. It is possible that tetraspanin webs stabilize the otherwise weak interaction between DM and MHC II, especially in ILVs (62). How this works in more multilamellar structures is unknown. The architecture of MIICs poses a problem when they fuse to the plasma membrane (as for MVBs or MIIC protruding tubules), because only the limiting membrane fuses with the plasma membrane. The interior components, including MHC-II, DM, and tetraspanin molecules, can then be secreted in the form of exosomes (63), and the ILV can fuse back to the limiting membranes of the MIIC. The details of this process are currently unclear. Some bacteria do not follow this route and bypass presentation. In one example, Salmonella-containing phagosomes have a structure that prevents interaction between MHC-II and DM, resulting in poor peptide loading of MHC-II in phagosomes (64). The exact order of antigenic protein proteolysis and the fate of resulting fragments within MIIC structures are unknown. The extent of fragmentation of the protein obviously depends on the location of the various unfoldases and proteases active in the late endosomal compartment. A critical unfoldase is the γ interferon–inducible protein IFI30/GILT, which reduces disulfide bonds to destabilize proteins for degradation by proteases (65). GILT is a soluble protein that—by simple diffusion—contacts all proteins entering the cell by endocytosis. The most prominent proteases in these late endosomal compartments are members of the cathepsin family (see below). These proteases are essentially soluble and are targeted to late endosomal compartments by the mannose6-phosphate receptor, which suggests that they catabolize proteins to generate peptide fragments in the luminal space of the MIIC. Fragments must then diffuse to MHC-II molecules for contact. Similar to the situation in the cytosol for MHC-I molecules (66), there are endosomal peptidases that may destroy a significant number of peptides before they will ever contact MHC-II, but they may also help in the generation of particular peptides (66). In sum, the MIIC is not a homogeneous late endosomal structure but contains different functional and structural domains. MHC-II and DM interact with tetraspanin proteins in a protein web on ILV, but MHC-II and DM can also be found on the luminal part of MIIC, where tetraspanin proteins are hardly found (67). These interactions between MHC-II and DM may be altered under infectious conditions that affect DMmediated peptide acquisition by MHC-II, as occurs in Salmonella-containing phagosomes (64). The details of MHC-II and DM interactions—and by default MHC-II peptide loading within the multidomain MIIC structure—are still poorly understood.

HOW TO GENERATE A PEPTIDE FOR MHC CLASS II: PROTEASES IN THE ENDOSOMAL SYSTEM AND HIGHER FORMS OF REGULATION When MHC-II arrives with Ii in the endosomal system, it is exposed to a series of proteases that degrade proteins and then generate and/or eliminate potential antigenic peptides for presentation. Late endosomes and lysosomes such as the MIIC are single membrane–limited cytoplasmic organelles with an acidic pH of approximately 3.8–5.0, and they contain endosomal proteases, primarily cathepsins. These include the serine proteases cathepsin A and G (catA and G), the aspartic proteases cathepsin D and E (pepsin family A1A), and 11 human cysteine cathepsins, B, C, F, H, K, L, O, S, V, X, and W (papain family C1A). An additional endosomal cysteine protease is legumain (Lgmn; asparagine endopeptidase) (family C13). Finally, there is the γ-IFN–inducible lysosomal thiol reductase GILT/IFI30, which is does not cleave peptide bonds but reduces the disulfide bond in proteins, which makes these proteins better substrates for the cathepsins. Proteases differ in their cellular and tissue distribution and substrate specificity, and these differences may influence the MHC-II peptidome. These issues are discussed here.



10.9

IY34CH10-Neefjes

ARI

11 February 2016

13:49

Cathepsins and MHC Class II Presentation


Although classical experiments with lysosomotropic agents indicated that lysosomal proteases generated antigens for MHC-II (57), exclusive roles for defined proteases have rarely been observed. The main lysosomal protease, catD, may be involved in antigen generation for MHC-II, but it may also destroy antigenic fragments (68). This illustrates the complex contribution of these enzymes to antigen processing for presentation. An important step in the life cycle of MHC-II is the removal of Ii in the MIIC. Ii is removed by degradation in a stepwise manner (with the CLIP fragment remaining in the MHC-II peptidebinding groove). CatS and, in cortical thymic epithelial cells, catL process Ii (69, 70). A failure to digest Ii in the cortical thymic epithelial cells of catL knockout mice affects MHC-II antigen presentation and the positive selection of CD4+ T cells (70). Although catS is critical in Ii degradation, catL can be replaced by catV (L2), which is also highly expressed in human thymus (71). CatF, catB, catD, and Lgmn are not critical for antigen generation and Ii degradation; their activity is probably replaced by other lysosomal proteases (31, 72). In summary, some proteases are essential for Ii and antigen processing for MHC-II presentation; most proteases are redundant.

Tissue Distribution, Structure, and Specificity of Cathepsins Many cathepsins are encoded in the human genome (73). An analysis—using the ImmGen immunotissue expression database (74) of relative expression in MHC-II–expressing APCs (DCs, macrophages, monocytes, and B cells)—reveals that these cells (with the exception of pro-B cells) all express Ii (CD74) and GILT (IFI30) at biologically relevant levels. Some cathepsins (catS, H, and C) have a similar expression profile, whereas other cathepsins (such as catL, E, and W) have a more narrow expression profile (Figure 5). ILCs, T cells, and stem cells do not express Ii, Lgmn, and catS, L, C, and O. Expression analysis of endosomal/lysosomal proteases in different MHC-II–expressing APCs indicates that the processing machinery for MHC-II peptides varies considerably between immune cell types. The efficiency of antigen fragmentation in these cell types may also differ. For example, macrophages are equipped with high levels of lysosomal proteases, whereas most DC types, monocytes, and B lymphocytes have substantially lower proteolytic capacity (75, 76) (Figure 5). Of note, high proteolytic activity is not necessarily beneficial for MHC-II antigen generation, as MHC-II binds a fragment rather than the final product of proteolysis: amino acids (68). In combination, the different cathepsins can cleave a diverse array of unfolded substrates. Collectively, this variety in the specificity of lysosomal cathepsins represents a comprehensive machinery to degrade proteins into smaller fragments; dipeptidases and other proteases complete the degradation to single amino acids, and in effect, they compete with MHC-II for peptide substrates. The structures of the different cathepsins explain their substrate specificities. The lysosomal cathepsins resemble the papain family of proteases, with two domains that open at the top forming the active-site cleft. The active-site cleft contains two catalytic residues, Cys25 and His163. These residues form the thiolate-imidazolium ion pair involved in the hydrolysis of peptide bonds from their substrates (Figure 6). Most cysteine cathepsins show endopeptidase activity, whereas catB, C, H, and X exhibit exopeptidase activity. Exopeptidases usually only allow the N- or C-terminal segment of a substrate to enter the active site’s cleft (77, 78), whereas the active site’s cleft extends along the whole length of the two-domain protease interface in endopeptidases (catF, L, K, S, and V) (79). CatC is an aminodipeptidase (78), catB is a carboxydipeptidase (77), and catX is a carboxymonopeptidase (80). It is likely that these exopeptidases serve to trim MHC-II–associated extended peptides. The (broad) substrate specificity of cathepsins is summarized in Figure 7. 10.10

Unanue

· · Turk

Neefjes


IY34CH10-Neefjes

ARI

11 February 2016

13:49

B cells

a

Stem cells

Pro-/Pre-

Mature

Dendritic cells

Macrophages Monocytes T cells

ILCs


li

Cathepsins

b li

Cystatins

Expression Low

High

Figure 5 Expression profiles of cathepsins in immune cells. (a) Expression profiles of cathepsins (Cts), legumain (Lgmn), GILT (IPI30), and the invariant chain (Ii; CD74). (b) Expression profiles of cystatins (Cst) and Ii (CD74) in various mouse and human primary immune cells (extracted from the ImmGen database). The cells are grouped, from left to right, according to cell type (indicated by the colored bars on top of the graph). This expression profile illustrates the variation between immune cells in the proteolytic machinery of the endosomal system, where MHC-II acquires peptides for presentation. Abbreviation: ILCl, innate lymphoid cell.



10.11

IY34CH10-Neefjes

ARI

11 February 2016

13:49

Cathepsin L-peptide substrate

Side chains and bonds


Amino acids

Figure 6 Model of a peptidyl substrate in the active site of cathepsin L, showing how cathepsin L interacts with a peptide substrate (depicted using a yellow ball-and-stick model). The surface of the active site is shown in gray, projected over the relevant amino acids of the active center (shown in green ball-and-stick form). The side chains in the active center that catalyze the cleavage of the peptide substrate (Q19, C25, H163, and W189) are shown in red, and their bonds with the peptide substrate are shown as dotted gray lines. All cysteine proteases have an active center for proteolytic activity, as shown here.

Regulation of Protease Activity Cathepsins are not always active, owing to various control mechanisms, such as pH, zymogen activation, and endogenous and exogenous inhibitors. This builds an additional layer of control and complexity and may also affect MHC-II antigen presentation. Cysteine cathepsins are synthesized as inactive enzymes called zymogens. Zymogens have a propeptide that folds on the surface of the enzyme and covers the catalytic site, thus blocking substrate access (81) and preventing premature proteolytic activity. The propeptide unfolds at acidic pH, opening the active site for protease activity (82). Propeptides can be removed by resident cathepsins or by the cysteine cathepsins themselves (catB, V, L, and S) when entering acidic compartments. This finding is important, as it implies that inhibiting one cathepsin can also affect the activation of another protease, if the propeptide of the latter is not removed by the inhibited enzyme. Thus, experiments inhibiting a single cathepsin need to be interpreted with caution, as the observed results may involve other proteases as well. Cystatins are natural high-affinity inhibitors of cathepsins and thus may affect MHC-II antigen presentation (83–85). Three cystatin families include inhibitory proteins: the stefins (type 1 cystatins), cystatins (type 2 cystatins), and kininogens (type 3 cystatins) (84, 85). Stefins are cytosolically/nuclearly expressed acidic proteins of ∼100 amino acids with broad specificity for cathepsins. Stefins probably prevent cathepsin activity in the cytosol upon rupture of lysosomes. More relevant to MHC-II antigen presentation, however, are cystatins. Cystatins are ∼120-amino-acid secreted proteins. Seven family members exist, with cystatin C (cst3) highly expressed in various immune cells (Figure 5). Cst3 is poorly expressed in B cells, indicating that this form of protease control varies among MHC-II–expressing APCs. Other cystatins are expressed only in particular activated immune cells (Figure 5). Cst3 is a broad inhibitor of cathepsins (86), including catS, which may (83) or may not (87) prevent Ii processing in mouse 10.12

Unanue

· · Turk

Neefjes


IY34CH10-Neefjes

ARI

11 February 2016

13:49

Position cleavage site S4


Enzyme class Aspartic endopeptidases

Cat D

Cysteine

Cat C Cat H

Cysteine

Cat B Cat X/Z Cat F Cat K

Cysteine endopeptidases

S2

S1

S1'

No K/R

No P

No P

S2'

Cat E

N-peptidases

C-peptidases

S3

Cat L Cat S Cat V Cat W

R Some “preference” Y, M,C

Amino acid class Hydrophobic Aromatic Basic Acidic Aliphatic Proline Charged

Figure 7 The substrate specificity of endosomal cathepsins relative to the cleavage site. S1–4 indicate the positions of the amino acids N terminal of the cleavage site, and S1 –S2 represent the amino acids C terminal of the cleavage site. The chemical nature of the amino acids is shown in the color key on the right. Faint colors indicate some preference for amino acid groups; bold colors indicate a requirement for specific amino acid groups. Often different chemical groups are preferred, as indicated. The different cathepsins are clustered according to their active center and nature. Different endopeptidases classes have different specificities, but specificities are similar within each class.

DCs. The third inhibitor family is the kininogens, which are multifunctional and multidomain glycoproteins. In humans, two types of kininogens exist: high-molecular-weight kininogens (HKs) and low-molecular-weight kininogens (LKs). Both HKs and LKs are composed of three cystatin-like domains; Salvesen et al. (88) demonstrated that two of these domains are inhibitors that simultaneously inhibit two cathepsin molecules (89). They are strong inhibitors of some, but not all, endoproteases. Although this hypothesis has not been tested, it stands to reason that kininogens may also influence the MHC-II–associated peptidome. Inhibition of the cathepsins that degrade Ii (catS and L) could affect MHC-II antigen presentation and be a useful way to control autoimmune diseases. Several inhibitors have been developed (reviewed in 90). These are either derivatives of active lead structures, such as the epoxysuccinylbased inhibitor E-64, or peptides with a reactive functional group, often referred to as a warhead, that covalently binds to the protease (these include leupeptin and halomethylketones). Also, the propeptides of the different cathepsins are being used as leads to generate new and specific cathepsin inhibitors (90). These and other structures have been developed to more selectively inhibit catS, with the goal of modulating Ii degradation and MHC-II antigen presentation (91). Although these inhibitors are active in the autoimmune mouse models of Sjogren’s disease (92) and lupus ¨ erythematosus nephritis (93), they have not yet entered clinical practice. However, these examples illustrate how chemical manipulation of the MHC-II pathway may find applications in the clinic. www.annualreviews.org • MHC-II Presentation


10.13

IY34CH10-Neefjes

ARI

11 February 2016

13:49


a

CatH-StefA

b

CatL-p41Ii

Figure 8 Interaction between cysteine cathepsins and their protein inhibitors. (a) Ribbon structure of cathepsin H (blue) in complex with stefin A ( yellow). A view across the active site’s cleft is shown, to indicate the three contact regions of stefins. The main chain of cathepsin H has an additional mini-chain, shown in cyan. The cysteine residue C25 of cathepsin H’s active site is shown in red (100; PDB 1NB5). Images were made in MAIN (Turk D. 2013. MAIN software for density averaging, model building, structure refinement and validation. Acta Crystallogr. D 69:1342–57). (b) Ribbon structure of cathepsin L (blue) in complex with the invariant chain p41 fragment ( yellow). The view across the active site’s cleft illustrates the same principle evident in stefin A’s binding to cathepsin H: Three binding loops at the bottom close the active site of the protease’s cleft. The cysteine in the cathepsin L active site is shown in red (101; PDB 1ICF).

The p41 Form of the Invariant Chain as a Protease Inhibitor Ii has various forms, including a large form, p41, characterized by the presence of an additional segment with significant homology to thyroglobulin type 1 domains; this segment inhibits cysteine cathepsins (94). The p41 fragment inhibits catL, V, K, and F, and to a lesser extent catS, but not catB, X, or C (94, 95). The functional role of the protease inhibitor domain spliced into Ii is not known; the p41 Ii form is only a minor species, and mice overexpressing it do not show a phenotype (96). Cystatins; stefins; and, to some extent, the thyroglobulin-type 1 domain of p41 share a similar mechanism of cathepsin inhibition (97–103) (Figure 8). Cystatins and stefins have a 5-stranded βpleated sheet wrapped around an extended α-helix, folded into a wedge-shaped edge with a flexible N-terminal segment. The first β-hairpin loop and N-terminal segment strongly interact with the active site of cathepsins to prevent access to substrates and effectively block proteolytic activity. On the other hand, the smaller p41 fragment consists of two disulfide-stabilized subdomains forming a small, wedge-shaped domain. The three binding loops of p41 Ii somewhat resemble the N-terminal segment and two hairpin loops of the cystatins (Figure 8). Thus, Ii is obviously not invariant, and one variant modulates proteolytic activity in the MIIC, and possibly MHC-II antigen presentation.

HOW TO LEAVE THE MHC CLASS II COMPARTMENT: COMPLEX TRANSPORT PATHWAYS AND FURTHER VARIATIONS Ultimately, MHC-II molecules are transported from proteolytic endosomal/lysosomal compartments to the cell surface. This transport may occur by direct transport and fusion of the MIIC to the plasma membrane (104) or may involve an intermediary tubulation step [as detected in activated DC (105, 106)]. In both cases, vesicles move in a bidirectional manner along microtubules, powered by various kinesin motors in the direction of the plasma membrane and by the dynein 10.14

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

motor in the direction of the nucleus (107, 108). Vesicles move in this complex dance until they meet the actin meshwork under the plasma membrane, where they bind to, and are retained by, actin motors (109). These motors include the actin motor MyoV, or Myo1e in the case of immature DCs (110). The actin meshwork must then dissolve to allow the MIIC or its tubules to contact the plasma membrane for fusion. Consequently, the other proteins of the MIIC are either released to the extracellular space (soluble proteins including the cathepsins) or enter the plasma membrane (membrane-bound proteins including MHC-II, DM, and the tetraspanins). The cathepsins are captured by recycling mannose-6-phosphate receptors, whereas transmembrane proteins, such as DM and tetraspanins, have internalization signals in their cytoplasmic tails that ensure swift endocytosis and migration to endosomal MIIC compartments. The protein content of the MIIC can thus be detected throughout the endosomal pathway, but concentrations are highest in the late endosomal MIIC compartment, with one notable exception. Unlike MHC-II, Ii contains internalization motifs (28). Because Ii is degraded in the MIIC, MHC-II will remain at the plasma membrane for antigen presentation until it is internalized by other mechanisms. This complex mode of vesicle transport is regulated by various small GTPases of the Rab, Arf, and Arf-like (Arl) family. These GTPases control the timing and transfer of MHC-II antigen presentation in various cells. Arl14 controls the release of the MIIC in immature DCs (110). Mature DCs deposited the intracellular pool of MHC-II at the plasma membrane, unlike immature DCs that retain a significant pool of MHC-II in the MIIC unless Arl14 is silenced. This has dramatic effects as immature DCs lacking the small GTPase Arl14 now have an MHC-II distribution similar to that of mature DCs. Arl14 is a GTPase in control of the MHC-II distribution in DCs (110). Likewise, Arl8b controls the motor protein KIF5 on the MIIC and also controls transport, cell surface expression, and antigen presentation by MHC-II molecules in DCs (111). These molecules are obviously regulated in a complex manner. The regulation of the dynein motor by Rab7 on the MIIC is the case that is best understood. Rab7 interacts with a cholesterol sensor, ORP1L, that controls the binding of the Rab7-associated dynein motor and the fusion of endosomes (112, 113). Further study of the complex transport route of the MIIC to the plasma membrane will define new mechanisms of control of MHC-II expression and antigen presentation.

PATHWAY VARIATIONS AND THEIR CONSEQUENCES FOR ANTIGEN PRESENTATION At first glance, the MHC-II antigen presentation system seems as though it should be very robust. To prevent autoimmune responses, the presentation of self-peptides should not vary; and to prevent differences in the response to a defined antigen presented by, for example, DCs rather than B cells, antigen peptide presentation should not vary. However, this presumption is challenged by various factors that increase variation in the MHC-II–presented peptidome and even the MHC-II molecule itself, with potential consequences for autoimmune responses.

Variations in Antigens: The Autophagic Delivery System for MHC Class II Antigen Presentation The MHC-II peptidome includes many peptides that derive from nuclear or cytosolic proteins. These peptides do not arrive in the MIIC by conventional endocytosis but instead through a process called autophagy (114). There are different forms of autophagy. In macro autophagy or canonical autophagy, proteins, protein aggregates, and nuclear material—and also entire organelles—are surrounded by a double membrane in an LC3/ubiquitin-dependent manner. This autophagosome then fuses with lysosomes, including the MIIC (to form autophagolysosomes), where the content is degraded (114–116). Macroautophagy is a constitutive process that occurs in all cells, but it www.annualreviews.org • MHC-II Presentation


10.15

ARI

11 February 2016

13:49

increases under conditions of cellular stress, including starvation. Of note, the general term autophagy also includes two other forms, microautophagy and chaperone-mediated autophagy, but whether they participate in MHC-II presentation is unclear. The idea that autophagy contributes to the MHC-II peptidome comes from several findings. Mass spectrometry shows that 20–30% of peptides isolated from MHC-II derive from cytosolic or nuclear proteins (117–120). Presentation of cytosolic proteins by MHC-II increased in response to the starvation of APCs, a process that induces autophagy (119). Several cytosolic proteins, some of which are hyperexpressed in APCs, are presented by MHC-II in a manner dependent on autophagy and prevented by autophagy inhibitor 3-methyladenosine (121–124). The Munz laboratory (125) detected the EBNA antigen from the Epstein Barr virus in autophagosomes and showed that MHC-II presentation of an EBNA1 epitope was partially inhibited by silencing the autophagy protein Atg12. They subsequently reported that autophagosomes bearing the autophagy protein LC3 could fuse to the MIIC (116). In fact, coupling a cytosolic antigen to the autophagy protein LC3 for targeting to autophagosomes induced MHC-II presentation of this antigen (116). These experiments connect autophagy to the MHC-II pathway for the delivery of cytosolic/nuclear antigens for presentation (Figure 3). The identification of peptides from the autophagy protein GABARAP (the mammalian ortholog of yeast ATG-8) in the MHC-II peptidome (117) further substantiates this point.


IY34CH10-Neefjes

Autophagy and Autoimmune-Associated Peptides Peptides with citrullinated residues are a unique set of antigens (126). This may be highly relevant, as autoantibodies recognizing citrullinated proteins are often found in rheumatoid arthritis (RA) and other autoimmune diseases. Citrullination is a post-translational modification (PTM), essentially occurring in the cytosol and nucleus, in which the amino acid arginine is converted to citrulline by peptidyl arginine deiminases, a small family of enzymes including PAD2 and PAD4 that are expressed in myeloid cells (127, 128). Autophagy would then provide a mechanism to deliver nuclear/cytosolic proteins citrullinated by PAD into the MHC-II pathway. Indeed, APCs expressing cytosolic lysozyme presented citrullinated, lysozyme-derived peptides in the context of MHC-II molecules that were recognized by CD4+ T cells (129). MHC-II presentation of the modified peptides required autophagy (129). Whether autophagy is critical for MHC-II presentation of all citrullinated peptides is unclear. The extent of autophagy differs in APCs from various tissues, which may translate into differences in MHC-II–controlled immune responses to some, especially nuclear and cytosolic, antigens. High levels of autophagy have been reported in thymic epithelial cells (130). These high levels may affect the thymic MHC-II peptidome and T cell selection, as observed in transgenic mice expressing GFP under the LC3 promoter. Unlike medullary epithelial cells, cortical thymic epithelial cells showed an active autophagy program (130–132), illustrating how this route of delivering antigens into the MHC-II pathway varies in different tissues that may have an effect on T cell selection.

The Distinct LC3-Associated Phagocytosis Pathway: Crossover Between Autophagy and Toll-Like Receptor Activation in Phagosomes APCs recognize and respond to pathogens, as detected by various Toll-like receptors (TLRs). Of these, TLR2 and 4 are essentially endosomal, phagosomal, and autophagolysosomal proteins; from these compartments, they signal the recognition of pathogen signals and then activate immune cells (133–135). This illustrates another combination of pathogen sensing in the same compartment where MHC-II could meet antigen. This process has been termed LC3-associated phagocytosis 10.16

Unanue

· · Turk

Neefjes


IY34CH10-Neefjes

ARI

11 February 2016

13:49

(LAP). LAP vesicles have a single membrane instead of the double membrane characteristic of canonical autophagosomes (135, 136). LAP occurs after the uptake of pathogens and results in the recruitment of NAPD-oxidase 2, which leads to a bactericidal oxidative burst (137). LAP also occurs after the engagement of Fc receptors from immune complexes (137), TIM4 from apoptotic cells (138), and the lectin protein dectin-1 after the uptake of fungi (139). Two studies have shown that mice with Atg5 deletions that reduce autophagy levels display variable degrees of impairment in MHC-II presentation of antigens regularly associated with LAP vesicles (136, 140). This further demonstrates that modulation of the endosomal-phagosomal pathway may have marked effects on the quality of MHC-II antigen presentation.


Transcriptional Regulation of MHC Class II Molecules and Beyond MHC-II α and β chain transcription, along with transcription of Ii and DM, is controlled by the transcriptional master regulator CIITA (for a review, see 141). In fact, CIITA is sufficient for MHC-II transcription and will induce MHC-II transcription in any cell type in which it is expressed. The CIITA gene itself has three different promoters, controlling the degree of expression in different tissues under regulation by various factors. Epigenetic factors ensure it is expressed only in immune cells; most cells lack CIITA expression. Many factors, including interferons, inflammatory signals, and interleukins, control CIITA expression. Their signals are transmitted by STAT (signal transducer and activator of transcription) 1 and IRF (interferon regulator factor)1 from signaling receptors, resulting in transcription of CIITA (141, 142). A genome-wide analysis has revealed that a complex interregulated pathway controls CIITA transcription. This analysis showed that various signaling pathways controlling MAP kinase and chromatin modifiers affect CIITA expression and thus MHC-II transcription (110). How the many factors controlling CIITA and MHC-II expression affect various APCs, as well as particular tumor types and cells in inflamed tissues, is still not fully understood. Transcription factors may also regulate the vesicular compartments involved in MHC-II antigen presentation. One such factor is the cytosolic transcription factor TFEB, which, after phosphorylation by the kinase ERK2 under conditions of starvation, is translocated into the nucleus. TFEB then starts a transcriptional program that induces/activates a series of proteases and the proton pump subunits of lysosomes (143). Activation of DCs by lipopolysaccharide (LPS) also induces nuclear import of TFEB and the initiation of the lysosomal activation transcription pathway. The resulting increase in lysosomal activity may foster MHC-II antigen presentation while reducing cross-presentation (144). The mechanism of transcriptional lysosomal and autophagy control is another factor contributing to the complexity of MHC-II antigen presentation.

Cell Biological Control of MHC Class II Complexity MHC-II presentation can also be controlled by alterations in the biology of APCs. This is best visualized for DCs when they convert from an immature to a more mature state (43, 44). Immature DCs have many MHC-II molecules in their MIICs and also at the cell surface. When activated by LPS and other factors, MHC-II translocates from its intracellular location to the cell surface, while at the same time extending its surface half-life and consequently prolonging and enhancing MHC-II presentation. It is likely that similar alterations in MHC-II cell biology occur during the activation of immature B cells, when MARCH-1 is downregulated (52). A study integrating a small interfering RNA (siRNA) screen with expression profiling revealed various proteins under the control of MHC-II in immature human DCs (110). These include a transcription factor (MAFA), PD-L1, and a small GTPase (Arl14) located in the MIIC. Silencing these factors in immature DCs generates changes in the MHC-II distribution typical of activated www.annualreviews.org • MHC-II Presentation


10.17

ARI

11 February 2016

13:49

DCs. Arl14 recruits the actin-based Myo1e motor for the intracellular retention of MIICs, and loss of this mechanism allows the release of intracellular MHC-II, even in immature DCs. There are other mechanisms of MHC-II control. Human monocytes downregulate MHC-II expression when exposed to IL-10 (which is generated by diverse stimuli, including pathogens). IL-10 arrests MHC-II export to the plasma membrane, at least in human monocytes, and reduces MHC-II antigen presentation (145). There are likely other mechanisms to downregulate MHC-II as well. Cholesterol is one such factor controlling MHC-II distribution and antigen presentation. MHC-II molecules may concentrate at the cell surface in cholesterol-containing microclusters that promote MHC-II antigen presentation to T cells (67). In addition, statins, frequently used to lower cholesterol levels, have been reported to downregulate MHC-II expression by affecting microdomains and possibly transport (146). Many other mechanisms affecting the intracellular transport of MHC-II are probably in play. These mechanisms include manipulation of intracellular compartments by bacterial pathogens such as Salmonella spp., Mycobacterium tuberculosis, Chlamydia, and others. Identifying how these pathogens conceal their antigen presentation may provide new insights into host pathways critical for MHC-II antigen presentation and could possibly yield strategies to combat these pathogens or manipulate MHC-II in autoimmune diseases.


IY34CH10-Neefjes

Variations in Antigen Targeting Antigens can enter the endocytic route in various ways. The most indiscriminate way is by bulk fluid endocytosis. Some cells, such as macrophages and immature DCs, have a high uptake capacity, whereas mature DCs and B cells take up smaller extracellular volumes. In the latter case, antigen acquisition is most efficient by receptor-mediated uptake. Cells have many receptors for antigens. B cells have the B cell receptor (BCR) for specific antigen uptake, whereas other APCs have one or more Fc receptors (for uptake of antibody-bound antigen) and one or more lectin receptors that recognize carbohydrates on antigens and microbes. The binding of receptors to antigen can affect the mode of degradation, as has been shown for antigens taken up by the BCR (147, 148). The BCR may bind to the proteolytic-sensitive sites of a protein, thus modifying its rate of degradation. It is likely that other receptor-antigen combinations also affect the mode of antigen degradation and then their presentation by MHC-II. However, efficient sampling and internalization of antigens obviously improves MHC-II antigen presentation when antigens are present in small amounts. BCRs ensure that the presentation of specific antigens is strongly favored, to allow activation of the correct CD4+ T cells and prevent activation by CD4+ T cells that do not recognize an antigen corresponding to that recognized by BCRs.

The Pathways of Presentation of Denatured Proteins or Peptides: Relevance to Autoimmunity The initial findings that defined antigen presentation indicated that the processing of proteins by APCs involved partial catabolism in acidic compartments of the cell, as described above. In these studies, a segment of a given protein was selected after processing by a defined MHC-II molecule, and this selection was reproduced by offering the corresponding peptide to an APC (149–152). Drugs that alkalinized intracellular vesicles blocked the presentation of peptides derived from protein processing; however, the drugs had no effect on the presentation of free peptides or denatured proteins. Even chemically fixed APCs presented peptides, indicating that binding and presentation occurred via plasma membrane MHC-II proteins (153). Subsequent studies identified denatured proteins (151, 154, 155) and proteins with conformational flexibility (156) that did not 10.18

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

undergo the same intracellular processing requirements as native proteins. These antigens bound directly to MHC-II molecules at the plasma membrane or early endosomes (155). To bind peptides at these sites, MHC-II molecules must first release their original content to generate an open groove for the next antigen. The MHC-II peptidome contains high-affinity peptides, but a significant number of low-affinity ones as well. The peptides in these low-affinity peptide–MHC complexes have fast dissociation rates and are rapidly destroyed by proteases when released (157, 158). This generates MHC-II molecules receptive to new antigenic fragments. This alternative way of peptide acquisition by MHC-II molecules can have important consequences for the resulting peptidome. Presentation of peptides or denatured proteins by plasma membrane MHC-II avoids DM editing. This mode of presentation results in a broader peptidome and in the development of CD4+ T cells that respond only to peptides or denatured proteins but not to native antigens. These unconventional T cells are thought to be reactive to protein epitopes that are not processed efficiently or are destroyed during the processing steps by APCs. These cells have been termed type B T cells to distinguish them from conventional type A T cells. Several investigators, most prominently Eli Sercarz, suggested that these T cells responded to “cryptic” determinants and envisioned that they would be relevant in cases of unresponsiveness—tolerance—to major determinants (159, 160). In one example of this, cryptic antigen presentation was found in MHC class II I-Ab haplotype mice in which a peptide derived from the I-Ab α chain elicited a response that could not be reproduced from the endogenous catabolism of this MHC class II chain expressed in an APC (161). A similar finding was made regarding a peptide processed from the β chain of I-Ak molecules (162). This lack of reactivity to determinants expressed after protein processing became very apparent in studies examining peptides processed from the small protein hen egg-white lysozyme (HEL) by MHC-II I-Ak or I-Ek molecules. Two T cell types were isolated, conventional T cells (type A) and T cells only reactive to the HEL peptide segment offered to an APC as a peptide or denatured protein (type B) (163–165). Thus, peptides/denatured proteins were handled differently from intact proteins, even when APCs were presenting the same peptide segment from both. HEL was processed in the MIIC, whereas peptide or denatured HEL also interacted with MHC-II in early endosomes or at the plasma membrane. Again, even in the absence of DM editing, particular peptides/denatured proteins were allowed to be presented in the context of MHC-II to initiate unique T cell responses. This mode of presentation of peptides or denatured proteins is important in the context of autoimmunity and infections. The evidence for this mode of presentation comes from two sets of studies: reports in which experimental animals were immunized to autologous proteins versus denatured proteins and reports in which autoreactive T cells were characterized in human or experimental autoimmunities. Reports in the early literature indicated that immunization with autologous proteins failed to induce an immune response—these are the early fundamental observations that defined the self– non-self paradigm in immunity. However, immunization with the same, but denatured, autologous protein resulted in antibody responses, as cited in Landsteiner’s classical monograph: The Specificity of Immunological Reactions. More recently, Weigle (166) reported that immunization of rabbits with autologous thyroglobulin did not elicit antibodies or thyroiditis, unlike immunization with the same protein in a denatured state. Delayed sensitivity in guinea pigs was observed with denatured autologous immunoglobulin but not with the native protein (167). In some strains of mice or guinea pigs, denatured insulin, but not native insulin, elicited responses (168, 169). Denatured antigens are thus handled differently by the immune system than their native counterparts. Consistent with these findings are the results of experiments with the model antigen HEL. In these studies, HEL was expressed as a transgenic protein in all APCs. Mice immunized with www.annualreviews.org • MHC-II Presentation


10.19

IY34CH10-Neefjes

ARI

11 February 2016

13:49


native HEL, now a self-protein, did not respond, whereas those immunized with denatured HEL or with HEL peptides did respond (170). In this situation, peptides from HEL were presented in the thymus via the conventional MHC-II peptide loading process, and CD4+ T cells recognizing these conventional peptides were eliminated by negative selection. However, the type B T cells recognizing a different form of the same antigen in the context of MHC-II were not negatively selected and were available to recognize MHC-II peptides in peripheral tissues, potentially causing autoimmune responses. In sum, the peptide repertoire from denatured proteins or peptides is different from and broader than that of native proteins and is not restricted by the complex nuances of antigen processing and peptide editing by DM that take place in the MIIC. As a result, control of self-reactivity can be lost when an autoreactive protein is presented as a denatured molecule (Figure 9). The presentation of self-epitopes by peptides or denatured self-antigens has now been documented in several autoimmune diseases in mice and humans (reviewed in 171). The bestdocumented case relates to spontaneous diabetic autoimmunity in NOD mice. NOD mice develop diabetes by approximately 16–24 weeks of age. The major autoantigen that drives the autoimmune process is insulin (172; reviewed in 173). Diabetogenic CD4+ T cells recognizing insulin peptides are found early in the disease process (171–173). Many of them recognize a segment from the B chain of the insulin. Generally, APCs that process insulin present a peptide encompassing the

T H YM US

PERIPH ERAL TIS S UE

Extracellular peptide generation Tissue-specific Ag mTEC

AIRE LE

Tissue-specific Ag

APC Endoso some me

Stable pt-loading

MHC-II

(Less) stable pt-loading

DM

Type A pMHC-II not recognized

Type A pMHC-II complex

Type B pMHC-II complex Type B T cell

Type A T cell

Type B T cell Deleted by apoptosis

Escapes negative selection Activation of type B T cell leading to autoimmune T cell response

Figure 9 The presentation of exogenous peptides or denatured proteins by MHC-II evades thymus control of autoreactivity. (Left) Tissuespecific antigens are presented in the thymus medullary epithelium under the control of the AIRE and other transcription factors. But denatured proteins and peptide fragments can be presented differently and not selected against in the thymus. (Right) A scenario for how these epitopes can be generated for MHC class II (MHC-II) presentation to nonconventional type B CD4+ T cells. Nonconventional CD4+ T cells are not negatively selected in the thymus, as the unedited peptides are not exposed by MHC-II. Abbreviations: Ag, antigen; APC, antigen-presenting cell; LE, late endosome; pMHC-II, peptide-loaded MHC-II; pt, peptide. 10.20

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

13–21 amino acid segment of the insulin B chain. This peptide is a relatively good binder to I-Ag7 , the key MHC-II molecule that gives NOD mice a high propensity for diabetes. However, CD4+ T cells reactive to the 13–21 peptide are found in low abundance and are poorly reactive because they are negatively selected in the thymus, through the presentation of insulin under AIRE control. Instead, the most abundant T cells are reactive to a closely related segment: 12–20. Peptide 12–20 is not found after insulin processing—it is only detected by T cells after interactions of APCs with free peptide or denatured insulin. T cells reactive to peptide 12–20 are relatively abundant and initiate diabetogenesis (173, 174). In sum, a single amino acid shift of the peptide position in the MHC-II binding groove induces a difference between recognition of self and non-self. In the MIIC, DM only favors the stronger 13–21 segment and deletes the weaker 12–20 segment, thus preventing diabetes. Further studies have shown that the β cells of the islets of Langerhans are the source of peptides derived from insulin catabolism. Secretory granules containing insulin catabolites are taken by local APCs that normally reside in islets and serve as the conduit from β cells to T cells (175). In conclusion, there is a repertoire of peptide–MHC-II complexes from denatured proteins or peptides that is unique to a pathway of exogenous antigen presentation. This peptide selfrepertoire may become significant in autoimmune situations, provided the tissue has a mechanism to generate denatured self-proteins or peptides and offer them to the immune system. This situation is evident in endocrine tissues, in which hormones are packaged in secretory granules that may release denatured fragments for presentation by resident MHC-II APCs. Whether it applies to other autoimmune diseases needs to be examined. However, these results may explain why most autoimmune diseases are strongly correlated with a specific MHC-II allele; unlike other MHC-II alleles, these risk-associated alleles would favor interactions with such autoimmune peptides. The relationship between the MHC-II risk-alleles molecules and their interaction with DM also need to be considered in future studies.

Beyond the Genetic Code: Post-Translational and Chemical Modifications of Antigens, and Relevance to Autoimmunity Proteins or peptides that are processed and presented by APCs on MHC-II can experience structural changes as a result of post-translational modifications (PTMs), or interactions with exogenous chemicals. An MHC-II–bound peptide can be modified, increasing the peptide repertoire for recognition by T cells and leading to wanted—but very often also unwanted—responses. PTM may take place as a result of oxidative or other chemical changes that take place as a peptide or protein moves through the various intracellular compartments of the APC. Among the changes reported for MHC-II–bound peptides are citrullination of arginines, oxidation of cysteines and tryptophans, iodination and nitration of tyrosines, deamidation of asparagines and glutamines, and glycosylation on serine and threonine residues (176, 177). PTM basically alters the peptide code, and PTMs can be specifically and exclusively recognized by CD4+ T cells (178, 179). PTM can affect antigen presentation in two ways: 1. A peptide may bind with poor affinity to MHC-II as a result of unfavorable MHC anchor residues after PTM; however, a chemical modification may also improve the affinity of an anchor residue for MHC-II, thus converting the peptide to a higher-affinity binder. Such improvements happen in the case of some citrullinated peptides (180). 2. PTM can alter TCR contact residues of the peptide and even flanking residues. In both cases, the resulting neopeptides may be recognized by T cells that escape thymic deletion, and this recognition may contribute to autoimmune responses (examples are found in 178, 179). In several autoimmune reactions, a contribution of PTMs has been described, but a www.annualreviews.org • MHC-II Presentation


10.21

ARI

11 February 2016

13:49

cause-effect relationship has not been unequivocally established. PTMs have also been described for antigens recognized by patients’ serum antibodies and serve as important markers of disease. Here, we briefly discuss selected PTMs that are part of autoimmune reactions. Citrullination was described in the section on autophagy. The participation of this modification in autoimmunity, and in particular in RA, has been extensively discussed (reviewed in 181). The MHC-II allele HLA-DR4 is strongly associated with RA (182). HLA-DR4 contains sequence motifs comprising residues that form a positively charged P4 MHC anchor site, one that excludes positively charged amino acids, such as arginines (183). However, the citrullinated product of arginine, citrulline, is noncharged and can bind with higher affinity to HLA-DR4 (180). Indeed, T cells specific to citrullinated peptides have been found in RA patients and in mice expressing RA susceptibility MHC-II molecules (180, 183–185). At present, findings establish correlation, not causality. In RA or in a model of collagen-induced arthritis, T cells and antibodies to collagen are implicated in pathogenesis. In mice, some T cells recognize glycosylated collagen epitopes in the context of MHC-II (186). The glycosylated peptides are expected to alter the MHC-II structure or affect TCR contact sites. Citrullination of peptides has also been discussed in the context of multiple sclerosis or experimental autoimmune encephalitis. The myelin basic protein—one of the main autoimmune targets—is rich in arginines, and many of these arginines are spontaneously modified to citrulline in vivo. Whether T cells reactive to citrullinated derivatives are critical for these diseases is an important issue to settle (187, 188). Another PTM occurring in peripheral tissue is the iodination of tyrosine residues in the thyroid, as a result of the production of the hormones tri- and tetraiodothyronine. Autoimmune thyroid disease was one of the first documented human autoimmune diseases, with both T and B cell autoreactivity associated with a particular MHC-II allele, HLA-DR3 (reviewed in 189). Proteins in the thyroid gland, such as thyroglobulin or thyroid peroxidase, have been implicated as major antigens for T cell responses. Their iodinated derivatives may be recognized by T cells, as suggested by studies of the mouse line NOD.h4, which develops spontaneous thyroiditis; this process is accelerated by addition of sodium iodide to the drinking water (190). The role of iodine in the development of this disease and the contribution of T cells specific to iodinated thyroglobulin peptides to autoimmune thyroid diseases have been much discussed. Iodinated residue–specific T cells have been documented, but their contribution is not yet clear (191). Just as endogenous proteins can be modified to generate an altered self-antigen, food proteins can be modified by host enzymes to induce autoimmunity in an MHC-II–restricted manner. This is best exemplified by celiac disease, in which inflammation of the intestinal epithelium is induced by ingestion of cereals containing gluten (192). Removal of gluten from the diet resolves the inflammation. Patients with celiac disease have a genetic predisposition; the disease displays a strong association with the MHC-II alleles HLA-DQ2 and HLA-DQ8 (193, 194). The disease has a complex biology that includes the presence of autoantibodies to transglutaminase 2 (Tg2), a ubiquitous enzyme responsible for the deamidation of glutamine to glutamic acid. The resulting removal of Tg2 also alters the normal conversion of glutamine. The modified gliadin peptides from gluten bind to HLA-DQ2 and HLA-DQ8, translating into T cell autoreactivity (195–198). This is one of the best examples in which we understand the chemical basis for the reactivity that results in autoimmunity: An antigen (gliadin) has been identified, a clear molecular understanding of the disorder has been obtained, and an easy solution exists (altered diet). Another surprising PTM can result from strong immune responses. APCs activated by microbial products, can produce reactive oxygen products and nitric oxide, which induce several strong oxidative molecules, including peroxynitrate. As a result, amino acids such as tryptophan can be oxidized, and tyrosine can be nitrated. Peptides bearing nitrotyrosine or oxidized tryptophan can


IY34CH10-Neefjes

10.22

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

be presented by MHC-II and recognized by highly specific T cells (178, 179). In one telling experiment, transgenic mice expressing the small protein HEL were infected with the intracellular pathogen Listeria monocytogenes. T cells reactive to the major nitrotyrosine-containing peptide processed from HEL were activated, while T cells reactive to the unmodified epitope remained inactive (179). Although this was a contrived situation, these results suggest that autoreactivity to modified self-proteins can take place during infections. Finally, species are always exposed to chemicals with variable chemical reactivity, cigarette smoke included. These exogenous chemicals can also modify antigens and evoke specific T cell responses. The first indications of antigen modifications by small chemicals came from the use of haptens. In a telling series of immunizations in guinea pigs, skin sensitivity reactions to azobenzenearsonate, a hapten bound to carrier proteins (199), were elicited. Other (ex vivo) studies found T cells specific to the hapten trinitrophenyl, chemically bound to MHC-II molecules (200). These results are highly relevant for understanding skin sensitivity reactions after contact with industrial or ambient products. One of the best studies of an immune response to chemicals in the environment (i.e., contact sensitivity) is study of beryllium (Be2+ ) hypersensitivity, which develops in industrial workers who handle Be2+ compounds. It results in serious chronic granulomatous lung disease and is associated with the MHC-II allele HLA-DP2 and the corresponding CD4+ T cells (201–203). Be2+ enters an acidic pocket in the HLA-DP2–peptide structure. This alters the shape of the HLA-DP2– peptide complex, which can be recognized by specific T cells that were not negatively selected in the thymus: The Be2+ -peptide combination was not present at that site during T cell selection (204). An estimated 10% of the human population is hypersensitive to nickel and other cations such as cadmium or gold. Such cations bind to the MHC-II molecules and/or associated peptide. The cation-modified peptide-MHC complex can then be recognized by CD4+ T cells that were not negatively selected by the thymus (reviewed in 205), analogous to Be2+ hypersensitivity. A role for T cells has also been reported in contact sensitivity to plant products, such as poison ivy, that produce urushiol, a catechol; however, the chemical basis of urushiol’s effect on MHC molecules has not been determined (206). Finally, one should note a related situation for peptides bound to MHC-I. Hypersensitivity to the antiretroviral drug abacavir is strongly associated with the HLA-B57:01 allele (207). The drug binds noncovalently inside the MHC-I peptide-binding groove and induces a specific change in the shape of the peptide (which is then considered novel by the immune system) that results in recognition by highly specific T cells. Similar interactions between drugs and MHC class II responses are expected. In summary, MHC-II peptide combinations can be altered by different chemical entities that either modify peptides or alter the shape of the peptide in MHC-II pathways. This is usually dependent on the MHC-II allele as well as on the peptide and explains why hypersensitivity to cations or other chemicals is usually detected for a few people whereas others remain insensitive to these chemicals. It also illustrates how posttranslational chemical modifications of MHC-II peptide combinations can induce autoimmune responses in particular individuals.

One Molecule, Many Polymorphisms, and Even More Variations: The MHC Class II System MHC-II molecules are central regulators of adaptive immune responses, and their biology has been studied in depth. However, they are complex, as they are encoded by different loci, and these loci are polymorphic. The net result is that most individuals will present multiple fragments www.annualreviews.org • MHC-II Presentation


10.23

IY34CH10-Neefjes

ARI

11 February 2016

13:49

of the same antigen. The generation of antigens is also complex because they are the substrates of different proteases potentially generating different peptide fragments. Several cellular sites may participate in the process of peptide selection. The chaperone DM plays an essential role in the selection of high-affinity (or better, low off-rate) peptides, a process modified by the cochaperone DO. These processes of peptide selection can also be modified by pathogens, chemicals, the metabolic state of cells, and other conditions that alter the MHC-II–presented peptidome, and the resulting alterations can cause autoimmune responses. Understanding the MHC-II pathway and its variations may allow us to reset MHC-II antigen presentation from an autoimmune situation to its healthy state. The variation in this system is becoming clear, and solutions will follow.


DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We thank Dusan Turk and Marlieke Jongsma for illustrations and Janet Casmaer for the final editing. This work was supported by an ERC grant, an NWO-TOP, and a Gravity grant to J.N.; ARRS grants to V.T. and Boris Turk; and grants from the National Institutes of Health (USA) and the Juvenile Diabetes Research Foundation to E.R.U. LITERATURE CITED 1. Neefjes J, Jongsma ML, Paul P, Bakke O. 2011. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat. Rev. Immunol. 11:823–36 2. Kambayashi T, Laufer TM. 2014. Atypical MHC class II–expressing antigen-presenting cells: Can anything replace a dendritic cell? Nat. Rev. Immunol. 14:719–30 3. Kared H, Camous X, Larbi A. 2014. T cells and their cytokines in persistent stimulation of the immune system. Curr. Opin. Immunol. 29:79–85 4. Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, et al. 2008. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLOS Genet. 4:e1000024 5. Dilthey A, Cox C, Iqbal Z, Nelson MR, McVean G. 2015. Improved genome inference in the MHC using a population reference graph. Nat. Genet. 47:682–88 6. Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, et al. 1994. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368:215–21 7. Beck S, Trowsdale J. 2000. The human major histocompatability complex: lessons from the DNA sequence. Annu. Rev. Genom. Hum. Genet. 1:117–37 8. Jardetzky TS, Brown JH, Gorga JC, Stern LJ, Urban RG, et al. 1996. Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II–like conformation for bound peptides. PNAS 93:734–38 9. Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG. 1994. Pool sequencing of natural HLADR, DQ, and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules. Immunogenetics 39:230–42 10. Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J. 2015. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33:169–200 11. Castellino F, Zappacosta F, Coligan JE, Germain RN. 1998. Large protein fragments as substrates for endocytic antigen capture by MHC class II molecules. J. Immunol. 161:4048–57 12. Sercarz EE, Maverakis E. 2003. MHC-guided processing: binding of large antigen fragments. Nat. Rev. Immunol. 3:621–29 10.24

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

13. Zhang P, Leu JI, Murphy ME, George DL, Marmorstein R. 2014. Crystal structure of the stressinducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. PLOS ONE 9:e103518 14. Hughes AL. 2002. Natural selection and the diversification of vertebrate immune effectors. Immunol. Rev. 190:161–68 15. Trowsdale J, Parham P. 2004. Mini-review: defense strategies and immunity-related genes. Eur. J. Immunol. 34:7–17 16. Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, et al. 2007. Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. PNAS 104:16221–26 17. Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK, et al. 2012. Crystal structure of the HLA-DMHLA-DR1 complex defines mechanisms for rapid peptide selection. Cell 151:1557–68 18. Boog CJ, Neefjes JJ, Boes J, Ploegh HL, Melief CJ. 1989. Specific immune responses restored by alteration in carbohydrate chains of surface molecules on antigen-presenting cells. Eur. J. Immunol. 19:537–42 19. Bolscher JG, van der Bijl MM, Neefjes JJ, Hall A, Smets LA, Ploegh HL. 1988. Ras (proto)oncogene induces N-linked carbohydrate modification: temporal relationship with induction of invasive potential. EMBO J. 7:3361–68 20. Neefjes JJ, De Bruijn ML, Boog CJ, Nieland JD, Boes J, et al. 1990. N-linked glycan modification on antigen-presenting cells restores an allospecific cytotoxic T cell response. J. Exp. Med. 171:583–88 21. Blum JS, Wearsch PA, Cresswell P. 2013. Pathways of antigen processing. Annu. Rev. Immunol. 31:443– 73 22. Roche PA, Marks MS, Cresswell P. 1991. Formation of a nine-subunit complex by HLA class II glycoproteins and the invariant chain. Nature 354:392–94 23. Romagnoli P, Germain RN. 1994. The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy. J. Exp. Med. 180:1107–13 24. Roche PA, Cresswell P. 1991. Proteolysis of the class II–associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules. PNAS 88:3150–54 25. Zhong G, Castellino F, Romagnoli P, Germain RN. 1996. Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II–associated invariant chain peptides (CLIP). J. Exp. Med. 184:2061–66 26. Neefjes JJ, Stollorz V, Peters PJ, Geuze HJ, Ploegh HL. 1990. The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell 61:171–83 27. Peters PJ, Neefjes JJ, Oorschot V, Ploegh HL, Geuze HJ. 1991. Segregation of MHC class II molecules from MHC class I molecules in the Golgi complex for transport to lysosomal compartments. Nature 349:669–76 28. Bakke O, Dobberstein B. 1990. MHC class II–associated invariant chain contains a sorting signal for endosomal compartments. Cell 63:707–16 29. Bikoff EK, Huang LY, Episkopou V, van Meerwijk J, Germain RN, Robertson EJ. 1993. Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression. J. Exp. Med. 177:1699–712 30. Viville S, Neefjes J, Lotteau V, Dierich A, Lemeur M, et al. 1993. Mice lacking the MHC class II– associated invariant chain. Cell 72:635–48 31. Villadangos JA, Bryant RA, Deussing J, Driessen C, Lennon-Dumenil AM, et al. 1999. Proteases involved in MHC class II antigen presentation. Immunol. Rev. 172:109–20 32. Bergmann H, Yabas M, Short A, Miosge L, Barthel N, et al. 2013. B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8− dendritic cells require the intramembrane endopeptidase SPPL2A. J. Exp. Med. 210:31–40 33. Beisner DR, Langerak P, Parker AE, Dahlberg C, Otero FJ, et al. 2013. The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. J. Exp. Med. 210:23–30 www.annualreviews.org • MHC-II Presentation


10.25

ARI

11 February 2016

13:49

34. Neefjes JJ, Ploegh HL. 1992. Inhibition of endosomal proteolytic activity by leupeptin blocks surface expression of MHC class II molecules and their conversion to SDS resistance αβ heterodimers in endosomes. EMBO J. 11:411–16 35. Ghosh P, Amaya M, Mellins E, Wiley DC. 1995. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3. Nature 378:457–62 36. Anders AK, Call MJ, Schulze MS, Fowler KD, Schubert DA, et al. 2011. HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide. Nat. Immunol. 12:54–61 37. Sherman MA, Weber DA, Jensen PE. 1995. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity 3:197–205 38. Mosyak L, Zaller DM, Wiley DC. 1998. The structure of HLA-DM, the peptide exchange catalyst that loads antigen onto class II MHC molecules during antigen presentation. Immunity 9:377–83 39. Fremont DH, Crawford F, Marrack P, Hendrickson WA, Kappler J. 1998. Crystal structure of mouse H2-M. Immunity 9:385–93 40. Doebele RC, Pashine A, Liu W, Zaller DM, Belmares M, et al. 2003. Point mutations in or near the antigen-binding groove of HLA-DR3 implicate class II–associated invariant chain peptide affinity as a constraint on MHC class II polymorphism. J. Immunol. 170:4683–92 41. Kropshofer H, Vogt AB, Moldenhauer G, Hammer J, Blum JS, Hammerling GJ. 1996. Editing of the HLA-DR–peptide repertoire by HLA-DM. EMBO J. 15:6144–54 42. Denzin LK, Cresswell P. 1995. HLA-DM induces CLIP dissociation from MHC class II αβ dimers and facilitates peptide loading. Cell 82:155–65 43. Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. 1997. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388:782–87 44. Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, et al. 1997. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388:787–92 45. Martin WD, Hicks GG, Mendiratta SK, Leva HI, Ruley HE, Van Kaer L. 1996. H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Cell 84:543–50 46. Chapman DC, Williams DB. 2010. ER quality control in the biogenesis of MHC class I molecules. Semin. Cell Dev. Biol. 21:512–19 47. Marks MS, Roche PA, van Donselaar E, Woodruff L, Peters PJ, Bonifacino JS. 1995. A lysosomal targeting signal in the cytoplasmic tail of the β chain directs HLA-DM to MHC class II compartments. J. Cell Biol. 131:351–69 48. De Gassart A, Camosseto V, Thibodeau J, Ceppi M, Catalan N, et al. 2008. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. PNAS 105:3491–96 49. Shin JS, Ebersold M, Pypaert M, Delamarre L, Hartley A, Mellman I. 2006. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444:115–18 50. Boname JM, Lehner PJ. 2011. What has the study of the K3 and K5 viral ubiquitin E3 ligases taught us about ubiquitin-mediated receptor regulation? Viruses 3:118–31 51. Lapaque N, Hutchinson JL, Jones DC, Meresse S, Holden DW, et al. 2009. Salmonella regulates polyubiquitination and surface expression of MHC class II antigens. PNAS 106:14052–57 52. Matsuki Y, Ohmura-Hoshino M, Goto E, Aoki M, Mito-Yoshida M, et al. 2007. Novel regulation of MHC class II function in B cells. EMBO J. 26:846–54 53. Cho KJ, Walseng E, Ishido S, Roche PA. 2015. Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells. PNAS 112:10449–54 54. van Niel G, Wubbolts R, Ten Broeke T, Buschow SI, Ossendorp FA, et al. 2006. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25:885–94 55. Amigorena S, Drake JR, Webster P, Mellman I. 1994. Transient accumulation of new class II MHC molecules in a novel endocytic compartment in B lymphocytes. Nature 369:113–20 56. Neefjes J. 1999. CIIV, MIIC and other compartments for MHC class II loading. Eur. J. Immunol. 29:1421–25 57. Allen PM, Unanue ER. 1984. Differential requirements for antigen processing by macrophages for lysozyme-specific T cell hybridomas. J. Immunol. 132:1077–79


IY34CH10-Neefjes

10.26

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

58. Pierre P, Denzin LK, Hammond C, Drake JR, Amigorena S, et al. 1996. HLA-DM is localized to conventional and unconventional MHC class II–containing endocytic compartments. Immunity 4:229– 39 59. Li M, Rong Y, Chuang YS, Peng D, Emr SD. 2015. Ubiquitin-dependent lysosomal membrane protein sorting and degradation. Mol. Cell 57:467–78 60. Sanderson F, Kleijmeer MJ, Kelly A, Verwoerd D, Tulp A, et al. 1994. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science 266:1566–69 61. Hammond C, Denzin LK, Pan M, Griffith JM, Geuze HJ, Cresswell P. 1998. The tetraspan protein CD82 is a resident of MHC class II compartments where it associates with HLA-DR, -DM, and -DO molecules. J. Immunol. 161:3282–91 62. Hoorn T, Paul P, Janssen L, Janssen H, Neefjes J. 2012. Dynamics within tetraspanin pairs affect MHC class II expression. J. Cell Sci. 125:328–39 63. Segura E, Guerin C, Hogg N, Amigorena S, Thery C. 2007. CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J. Immunol. 179:1489–96 64. Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J, et al. 2005. Spatial separation of HLADM/HLA-DR interactions within MIIC and phagosome-induced immune escape. Immunity 22:221–33 65. Arunachalam B, Phan UT, Geuze HJ, Cresswell P. 2000. Enzymatic reduction of disulfide bonds in lysosomes: characterization of a γ-interferon–inducible lysosomal thiol reductase (GILT). PNAS 97:745– 50 66. Fernandez-Borja M, Verwoerd D, Sanderson F, Aerts H, Trowsdale J, et al. 1996. HLA-DM and MHC class II molecules co-distribute with peptidase-containing lysosomal subcompartments. Int. Immunol. 8:625–40 67. Bosch B, Berger AC, Khandelwal S, Heipertz EL, Scharf B, et al. 2013. Disruption of multivesicular body vesicles does not affect major histocompatibility complex (MHC) class II–peptide complex formation and antigen presentation by dendritic cells. J. Biol. Chem. 288:24286–92 68. Moss CX, Villadangos JA, Watts C. 2005. Destructive potential of the aspartyl protease cathepsin D in MHC class II–restricted antigen processing. Eur. J. Immunol. 35:3442–51 69. Shi GP, Villadangos JA, Dranoff G, Small C, Gu L, et al. 1999. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10:197–206 70. Nakagawa TY, Brissette WH, Lira PD, Griffiths RJ, Petrushova N, et al. 1999. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity 10:207–17 71. Tolosa E, Li W, Yasuda Y, Wienhold W, Denzin LK, et al. 2003. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J. Clin. Investig. 112:517–26 72. Yamamoto K, Kawakubo T, Yasukochi A, Tsukuba T. 2012. Emerging roles of cathepsin E in host defense mechanisms. Biochim. Biophys. Acta 1824:105–12 73. Rossi A, Deveraux Q, Turk B, Sali A. 2004. Comprehensive search for cysteine cathepsins in the human genome. Biol. Chem. 385:363–72 74. Heng TS, Painter MW. 2008. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9:1091–94 75. Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES. 2005. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307:1630–34 76. McCurley N, Mellman I. 2010. Monocyte-derived dendritic cells exhibit increased levels of lysosomal proteolysis as compared to other human dendritic cell populations. PLOS ONE 5:e11949 77. Musil D, Zucic D, Turk D, Engh RA, Mayr I, et al. 1991. The refined 2.15 A˚ X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity. EMBO J. 10:2321–30 78. Turk D, Janjic V, Stern I, Podobnik M, Lamba D, et al. 2001. Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. EMBO J. 20:6570–82 79. Turk D, Guncar G. 2003. Lysosomal cysteine proteases (cathepsins): promising drug targets. Acta Crystallogr. D 59:203–13 www.annualreviews.org • MHC-II Presentation


10.27

ARI

11 February 2016

13:49

80. Nagler DK, Zhang R, Tam W, Sulea T, Purisima EO, Menard R. 1999. Human cathepsin X: a cysteine protease with unique carboxypeptidase activity. Biochemistry 38:12648–54 81. Groves MR, Coulombe R, Jenkins J, Cygler M. 1998. Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes. Proteins 32:504–14 82. Jerala R, Zerovnik E, Kidric J, Turk V. 1998. pH-induced conformational transitions of the propeptide of human cathepsin L: a role for a molten globule state in zymogen activation. J. Biol. Chem. 273:11498–504 83. Pierre P, Mellman I. 1998. Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell 93:1135–45 84. Abrahamson M, Alvarez-Fernandez M, Nathanson CM. 2003. Cystatins. Biochem. Soc. Symp. 2003:179– 99 85. Turk V, Stoka V, Turk D. 2008. Cystatins: biochemical and structural properties, and medical relevance. Front. Biosci. 13:5406–20 86. Hall A, Hakansson K, Mason RW, Grubb A, Abrahamson M. 1995. Structural basis for the biological specificity of cystatin C: identification of leucine 9 in the N-terminal binding region as a selectivityconferring residue in the inhibition of mammalian cysteine peptidases. J. Biol. Chem. 270:5115–21 87. El-Sukkari D, Wilson NS, Hakansson K, Steptoe RJ, Grubb A, et al. 2003. The protease inhibitor cystatin C is differentially expressed among dendritic cell populations, but does not control antigen presentation. J. Immunol. 171:5003–11 88. Salvesen G, Parkes C, Abrahamson M, Grubb A, Barrett AJ. 1986. Human low-Mr kininogen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. Biochem. J. 234:429–34 89. Turk B, Stoka V, Turk V, Johansson G, Cazzulo JJ, Bjork I. 1996. High-molecular-weight kininogen binds two molecules of cysteine proteinases with different rate constants. FEBS Lett. 391:109–12 90. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, et al. 2012. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim. Biophys. Acta 1824:68–88 91. Wiener JJ, Sun S, Thurmond RL. 2010. Recent advances in the design of cathepsin S inhibitors. Curr. Top. Med. Chem. 10:717–32 92. Saegusa K, Ishimaru N, Yanagi K, Arakaki R, Ogawa K, et al. 2002. Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J. Clin. Investig. 110:361–69 93. Rupanagudi KV, Kulkarni OP, Lichtnekert J, Darisipudi MN, Mulay SR, et al. 2015. Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II–mediated CD4 T cell and B cell priming. Ann. Rheum. Dis. 74:452–63 94. Bevec T, Stoka V, Pungercic G, Dolenc I, Turk V. 1996. Major histocompatibility complex class II– associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J. Exp. Med. 183:1331–38 95. Mihelic M, Dobersek A, Guncar G, Turk D. 2008. Inhibitory fragment from the p41 form of invariant chain can regulate activity of cysteine cathepsins in antigen presentation. J. Biol. Chem. 283:14453–60 96. Shachar I, Elliott EA, Chasnoff B, Grewal IS, Flavell RA. 1995. Reconstitution of invariant chain function in transgenic mice in vivo by individual p31 and p41 isoforms. Immunity 3:373–83 97. Schuttelkopf AW, Hamilton G, Watts C, van Aalten DM. 2006. Structural basis of reduction-dependent activation of human cystatin F. J. Biol. Chem. 281:16570–75 98. Alvarez-Fernandez M, Liang YH, Abrahamson M, Su XD. 2005. Crystal structure of human cystatin D, a cysteine peptidase inhibitor with restricted inhibition profile. J. Biol. Chem. 280:18221–28 99. Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A, et al. 2001. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat. Struct. Biol. 8:316–20 100. Jenko S, Dolenc I, Guncar G, Dobersek A, Podobnik M, Turk D. 2003. Crystal structure of stefin A in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo- and exopeptidases. J. Mol. Biol. 326:875–85 101. Guncar G, Pungercic G, Klemencic I, Turk V, Turk D. 1999. Crystal structure of MHC class II– associated p41 Ii fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S. EMBO J. 18:793–803 102. Bode W, Engh R, Musil D, Thiele U, Huber R, et al. 1988. The 2.0 A˚ X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. EMBO J. 7:2593–99


IY34CH10-Neefjes

10.28

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

103. Stubbs MT, Laber B, Bode W, Huber R, Jerala R, et al. 1990. The refined 2.4 A˚ X-ray crystal structure of recombinant human stefin B in complex with the cysteine proteinase papain: a novel type of proteinase inhibitor interaction. EMBO J. 9:1939–47 104. Wubbolts R, Fernandez-Borja M, Oomen L, Verwoerd D, Janssen H, et al. 1996. Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface. J. Cell Biol. 135:611– 22 105. Kleijmeer M, Ramm G, Schuurhuis D, Griffith J, Rescigno M, et al. 2001. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. J. Cell Biol. 155:53–63 106. Boes M, Cerny J, Massol R, Op den Brouw M, Kirchhausen T, et al. 2002. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418:983–88 107. Wubbolts R, Fernandez-Borja M, Jordens I, Reits E, Dusseljee S, et al. 1999. Opposing motor activities of dynein and kinesin determine retention and transport of MHC class II–containing compartments. J. Cell Sci. 112(Pt. 6):785–95 108. Roche PA, Furuta K. 2015. The ins and outs of MHC class II–mediated antigen processing and presentation. Nat. Rev. Immunol. 15:203–16 109. Rocha N, Neefjes J. 2008. MHC class II molecules on the move for successful antigen presentation. EMBO J. 27:1–5 110. Paul P, van den Hoorn T, Jongsma ML, Bakker MJ, Hengeveld R, et al. 2011. A genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell 145:268–83 111. Michelet X, Garg S, Wolf BJ, Tuli A, Ricciardi-Castagnoli P, Brenner MB. 2015. MHC class II presentation is controlled by the lysosomal small GTPase, Arl8b. J. Immunol. 194:2079–88 112. van der Kant R, Fish A, Janssen L, Janssen H, Krom S, et al. 2013. Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L. J. Cell Sci. 126:3462–74 113. Rocha N, Kuijl C, van der Kant R, Janssen L, Houben D, et al. 2009. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150Glued and late endosome positioning. J. Cell Biol. 185:1209–25 114. Deretic V, Saitoh T, Akira S. 2013. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13:722–37 115. Strawbridge AB, Blum JS. 2007. Autophagy in MHC class II antigen processing. Curr. Opin. Immunol. 19:87–92 116. Schmid D, Pypaert M, Munz C. 2007. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26:79–92 117. Suri A, Walters JJ, Rohrs HW, Gross ML, Unanue ER. 2008. First signature of islet β-cell–derived naturally processed peptides selected by diabetogenic class II MHC molecules. J. Immunol. 180:3849–56 118. Dongre AR, Kovats S, deRoos P, McCormack AL, Nakagawa T, et al. 2001. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31:1485–94 119. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, et al. 2005. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. PNAS 102:7922–27 120. Chicz RM, Urban RG, Gorga JC, Vignali DA, Lane WS, Strominger JL. 1993. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J. Exp. Med. 178:27–47 121. Lich JD, Elliott JF, Blum JS. 2000. Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. J. Exp. Med. 191:1513–24 122. Jaraquemada D, Marti M, Long EO. 1990. An endogenous processing pathway in vaccinia virus–infected cells for presentation of cytoplasmic antigens to class II–restricted T cells. J. Exp. Med. 172:947–54 123. Bonifaz LC, Arzate S, Moreno J. 1999. Endogenous and exogenous forms of the same antigen are processed from different pools to bind MHC class II molecules in endocytic compartments. Eur. J. Immunol. 29:119–31 124. Malnati MS, Marti M, LaVaute T, Jaraquemada D, Biddison W, et al. 1992. Processing pathways for presentation of cytosolic antigen to MHC class II–restricted T cells. Nature 357:702–4 125. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, et al. 2005. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307:593–96 www.annualreviews.org • MHC-II Presentation


10.29

ARI

11 February 2016

13:49

126. Ireland JM, Unanue ER. 2011. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med. 208:2625–32 127. Vossenaar ER, van Venrooij WJ. 2004. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res. Ther. 6:107–11 128. Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L. 2008. Immunity to citrullinated proteins in rheumatoid arthritis. Annu. Rev. Immunol. 26:651–75 129. Ireland J, Herzog J, Unanue ER. 2006. Cutting edge: Unique T cells that recognize citrullinated peptides are a feature of protein immunization. J. Immunol. 177:1421–25 130. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. 2004. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15:1101–11 131. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. 2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:396–400 132. Aichinger M, Wu C, Nedjic J, Klein L. 2013. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210:287–300 133. Munz C. 2015. Of LAP, CUPS, and DRibbles—unconventional use of autophagy proteins for MHC restricted antigen presentation. Front. Immunol. 6:200 134. Mehta P, Henault J, Kolbeck R, Sanjuan MA. 2014. Noncanonical autophagy: one small step for LC3, one giant leap for immunity. Curr. Opin. Immunol. 26:69–75 135. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, et al. 2007. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–57 136. Romao S, Gasser N, Becker AC, Guhl B, Bajagic M, et al. 2013. Autophagy proteins stabilize pathogencontaining phagosomes for prolonged MHC II antigen processing. J. Cell Biol. 203:757–66 137. Huang J, Brumell JH. 2014. Bacteria-autophagy interplay: a battle for survival. Nat. Rev. Microbiol. 12:101–14 138. Florey O, Kim SE, Sandoval CP, Haynes CM, Overholtzer M. 2011. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat. Cell Biol. 13:1335– 43 139. Ma J, Becker C, Lowell CA, Underhill DM. 2012. Dectin-1–triggered recruitment of light chain 3 protein to phagosomes facilitates major histocompatibility complex class II presentation of fungal-derived antigens. J. Biol. Chem. 287:34149–56 140. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, et al. 2010. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32:227–39 141. Reith W, LeibundGut-Landmann S, Waldburger JM. 2005. Regulation of MHC class II gene expression by the class II transactivator. Nat. Rev. Immunol. 5:793–806 142. Wright KL, Ting JP. 2006. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol. 27:405– 12 143. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33 144. Samie M, Cresswell P. 2015. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen–presentation pathways. Nat. Immunol. 16:729–36 145. Koppelman B, Neefjes JJ, de Vries JE, de Waal Malefyt R. 1997. Interleukin-10 down-regulates MHC class II αβ peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity 7:861–71 146. Kuipers HF, Biesta PJ, Groothuis TA, Neefjes JJ, Mommaas AM, van den Elsen PJ. 2005. Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterolcontaining microdomains. Hum. Immunol. 66:653–65 147. Watts C, Lanzavecchia A. 1993. Suppressive effect of antibody on processing of T cell epitopes. J. Exp. Med. 178:1459–63 148. Simitsek PD, Campbell DG, Lanzavecchia A, Fairweather N, Watts C. 1995. Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. J. Exp. Med. 181:1957–63


IY34CH10-Neefjes

10.30

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

149. Ziegler HK, Unanue ER. 1982. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. PNAS 79:175–78 150. Chesnut RW, Colon SM, Grey HM. 1982. Requirements for the processing of antigens by antigenpresenting B cells. I. Functional comparison of B cell tumors and macrophages. J. Immunol. 129:2382–88 151. Allen PM, Strydom DJ, Unanue ER. 1984. Processing of lysozyme by macrophages: identification of the determinant recognized by two T-cell hybridomas. PNAS 81:2489–93 152. Shimonkevitz R, Colon S, Kappler JW, Marrack P, Grey HM. 1984. Antigen recognition by H-2– restricted T cells. II. A tryptic ovalbumin peptide that substitutes for processed antigen. J. Immunol. 133:2067–74 153. Ziegler K, Unanue ER. 1981. Identification of a macrophage antigen-processing event required for I-region–restricted antigen presentation to T lymphocytes. J. Immunol. 127:1869–75 154. Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M, et al. 1997. HLA-DR–restricted presentation of purified myelin basic protein is independent of intracellular processing. Eur. J. Immunol. 27:941–51 155. Lindner R, Unanue ER. 1996. Distinct antigen MHC class II complexes generated by separate processing pathways. EMBO J. 15:6910–20 156. Lee P, Matsueda GR, Allen PM. 1988. T cell recognition of fibrinogen: A determinant on the A α-chain does not require processing. J. Immunol. 140:1063–68 157. Donermeyer DL, Allen PM. 1989. Binding to Ia protects an immunogenic peptide from proteolytic degradation. J. Immunol. 142:1063–68 158. Carrasco-Marin E, Petzold S, Unanue ER. 1999. Two structural states of complexes of peptide and class II major histocompatibility complex revealed by photoaffinity-labeled peptides. J. Biol. Chem. 274:31333– 40 159. Cabaniols JP, Cibotti R, Kourilsky P, Kosmatopoulos K, Kanellopoulos JM. 1994. Dose-dependent T cell tolerance to an immunodominant self peptide. Eur. J. Immunol. 24:1743–49 160. Gammon G, Sercarz E. 1989. How some T cells escape tolerance induction. Nature 342:183–85 161. Barlow AK, He X, Janeway C Jr. 1998. Exogenously provided peptides of a self-antigen can be processed into forms that are recognized by self-T cells. J. Exp. Med. 187:1403–15 162. Lovitch SB, Walters JJ, Gross ML, Unanue ER. 2003. APCs present Aβk -derived peptides that are autoantigenic to type B T cells. J. Immunol. 170:4155–60 163. Viner NJ, Nelson CA, Deck B, Unanue ER. 1996. Complexes generated by the binding of free peptides to class II MHC molecules are antigenically diverse compared with those generated by intracellular processing. J. Immunol. 156:2365–68 164. Pu Z, Carrero JA, Unanue ER. 2002. Distinct recognition by two subsets of T cells of an MHC class II–peptide complex. PNAS 99:8844–49 165. Pu Z, Lovitch SB, Bikoff EK, Unanue ER. 2004. T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM. Immunity 20:467–76 166. Weigle WO. 1965. The induction of autoimmunity in rabbits following injection of heterologous or altered homologous thyroglobulin. J. Exp. Med. 121:289–308 167. McCluskey RT, Miller F, Benacerraf B. 1962. Sensitization to denatured autologous γ globulin. J. Exp. Med. 115:253–73 168. Rosenthal AS, Barcinski MA, Blake JT. 1977. Determinant selection is a macrophage dependent immune response gene function. Nature 267:156–58 169. Thomas JW, George-Gattner H, Danho W. 1989. T cells recognize both conformational and cryptic determinants on the insulin molecule. Eur. J. Immunol. 19:557–58 170. Peterson DA, DiPaolo RJ, Kanagawa O, Unanue ER. 1999. Quantitative analysis of the T cell repertoire that escapes negative selection. Immunity 11:453–62 171. Wegmann DR, Norbury-Glaser M, Daniel D. 1994. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur. J. Immunol. 24:1853–57 172. Daniel D, Gill RG, Schloot N, Wegmann D. 1995. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur. J. Immunol. 25:1056–62 www.annualreviews.org • MHC-II Presentation


10.31

ARI

11 February 2016

13:49

173. Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. 2010. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat. Immunol. 11:350–54 174. Mohan JF, Petzold SJ, Unanue ER. 2011. Register shifting of an insulin peptide–MHC complex allows diabetogenic T cells to escape thymic deletion. J. Exp. Med. 208:2375–83 175. Unanue ER. 2014. Antigen presentation in the autoimmune diabetes of the NOD mouse. Annu. Rev. Immunol. 32:579–608 176. Anderton SM. 2004. Post-translational modifications of self antigens: implications for autoimmunity. Curr. Opin. Immunol. 16:753–58 177. Petersen J, Purcell AW, Rossjohn J. 2009. Post-translationally modified T cell epitopes: immune recognition and immunotherapy. J. Mol. Med. 87:1045–51 178. Birnboim HC, Lemay AM, Lam DK, Goldstein R, Webb JR. 2003. Cutting edge: MHC class II– restricted peptides containing the inflammation-associated marker 3-nitrotyrosine evade central tolerance and elicit a robust cell-mediated immune response. J. Immunol. 171:528–32 179. Herzog J, Maekawa Y, Cirrito TP, Illian BS, Unanue ER. 2005. Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells. PNAS 102:7928–33 180. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. 2003. Cutting edge: The conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis– associated HLA-DRB1∗ 0401 MHC class II molecule. J. Immunol. 171:538–41 181. Koning F, Thomas R, Rossjohn J, Toes RE. 2015. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat. Rev. Rheumatol. 11:450–61 182. Gregersen PK, Goyert SM, Song QL, Silver J. 1987. Microheterogeneity of HLA-DR4 haplotypes: DNA sequence analysis of LD“KT2” and LD“TAS” haplotypes. Hum. Immunol. 19:287–92 183. Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, et al. 2013. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210:2569–82 184. Cordova KN, Willis VC, Haskins K, Holers VM. 2013. A citrullinated fibrinogen–specific T cell line enhances autoimmune arthritis in a mouse model of rheumatoid arthritis. J. Immunol. 190:1457–65 185. James EA, Rieck M, Pieper J, Gebe JA, Yue BB, et al. 2014. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 66:1712–22 186. Backlund J, Carlsen S, Hoger T, Holm B, Fugger L, et al. 2002. Predominant selection of T cells specific for the glycosylated collagen type II epitope (263–270) in humanized transgenic mice and in rheumatoid arthritis. PNAS 99:9960–65 187. Cao L, Sun D, Whitaker JN. 1998. Citrullinated myelin basic protein induces experimental autoimmune encephalomyelitis in Lewis rats through a diverse T cell repertoire. J. Neuroimmunol. 88:21–29 188. Moscarello MA, Mastronardi FG, Wood DD. 2007. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 32:251–56 189. Rose NR. 2011. The genetics of autoimmune thyroiditis: the first decade. J. Autoimmun. 37:88–94 190. Braley-Mullen H, Yu S. 2015. NOD.H-2h4 mice: an important and underutilized animal model of autoimmune thyroiditis and Sjogren’s syndrome. Adv. Immunol. 126:1–43 191. Kolypetri P, Carayanniotis K, Rahman S, Georghiou PE, Magafa V, et al. 2014. The thyroxinecontaining thyroglobulin peptide (aa 2549–2560) is a target epitope in iodide-accelerated spontaneous autoimmune thyroiditis. J. Immunol. 193:96–101 192. Sollid LM, Jabri B. 2011. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr. Opin. Immunol. 23:732–38 193. Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM. 2009. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat. Immunol. 10:1096–101 194. Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S, et al. 2008. The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456:534–38


IY34CH10-Neefjes

10.32

Unanue

· · Turk

Neefjes



IY34CH10-Neefjes

ARI

11 February 2016

13:49

195. Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, et al. 1998. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4:713–17 196. Qiao SW, Bergseng E, Molberg O, Jung G, Fleckenstein B, Sollid LM. 2005. Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J. Immunol. 175:254–61 197. Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, et al. 2010. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl. Med. 2:41ra51 198. Petersen J, Montserrat V, Mujico JR, Loh KL, Beringer DX, et al. 2014. T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat. Struct. Mol. Biol. 21:480–88 199. Jones VE, Leskowitz S. 1965. Role of the carrier in development of delayed sensitivity to the azophenylarsonate group. Nature 207:596–97 200. Thomas DW. 1978. Hapten-specific T lymphocyte activation by glutaraldehyde-treated macrophages: an argument against antigen processing by macrophages. J. Immunol. 121:1760–66 201. Falta MT, Pinilla C, Mack DG, Tinega AN, Crawford F, et al. 2013. Identification of berylliumdependent peptides recognized by CD4+ T cells in chronic beryllium disease. J. Exp. Med. 210:1403–18 202. Fontenot AP, Keizer TS, McCleskey M, Mack DG, Meza-Romero R, et al. 2006. Recombinant HLADP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells. J. Immunol. 177:3874–83 203. Bill JR, Mack DG, Falta MT, Maier LA, Sullivan AK, et al. 2005. Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II β-chain. J. Immunol. 175:7029–37 204. Clayton GM, Wang Y, Crawford F, Novikov A, Wimberly BT, et al. 2014. Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132–42 205. Wang Y, Dai S. 2013. Structural basis of metal hypersensitivity. Immunol. Res. 55:83–90 206. Kalish RS, Johnson KL. 1990. Enrichment and function of urushiol (poison ivy)-specific T lymphocytes in lesions of allergic contact dermatitis to urushiol. J. Immunol. 145:3706–13 207. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, et al. 2012. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486:554–58



10.33

Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation.

The ins and outs of MHC class II-mediated antigen processing and presentation.

MHC class II-restricted presentation of intracellular antigen.

Processing pathways for presentation of cytosolic antigen to MHC class II-restricted T cells.

ATGs help MHC class II, but inhibit MHC class I antigen presentation.

A central role for HSC70 in regulating antigen trafficking and MHC class II presentation.

Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation.

MHC class II-derived peptides can bind to class II molecules, including self molecules, and prevent antigen presentation.

Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells.

Viral immune evasion: Lessons in MHC class I antigen presentation.

Early BCR Events and Antigen Capture, Processing, and Loading on MHC Class II on B Cells.

Class I myosin Myo1e regulates TLR4-triggered macrophage spreading, chemokine release, and antigen presentation via MHC class II.

Anti-TNF monoclonal antibodies prevent haemorrhage-induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression.

High efficiency of endogenous antigen presentation by MHC class II molecules.

Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation.

MHC class II antigen presentation by dendritic cells regulated through endosomal sorting.

[A new mechanism of autoantibody production: antigen presentation of misfolded protein by MHC class II].

Class II MHC molecules can use the endogenous pathway of antigen presentation.

Toward a Network Model of MHC Class II-Restricted Antigen Processing.

The MHC class II antigen presentation pathway in human monocytes differs by subset and is regulated by cytokines.

Electroporation of exogenous antigen into the cytosol for antigen processing and class I major histocompatibility complex (MHC) presentation: weak base amines and hypothermia (18 degrees C) inhibit the class I MHC processing pathway.

Effect of isotypic and allotypic variations of MHC class II molecules on staphylococcal enterotoxin presentation to murine T cells.

Defects in antigen presentation of mutant influenza haemagglutinins are reversed by mutations in the MHC class II molecule.

Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control.