The FASEB Journal • SRC Commentary
Meeting Report on Immunoreceptors 2014 Toine ten Broeke,* Annemiek van Spriel,† Peter Sun,‡ and Jeanette Leusen*,1 *Laboratory of Translational Immunology, Immunotherapy Group, University Medical Center Utrecht, Utrecht, The Netherlands; †Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; and ‡Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Attendees of the FASEB Science Research Conference: Immunoreceptors (June 15–20, 2014) in Steamboat Springs, CO, USA.
THE 2014 FASEB SCIENCE Research Conference (SRC) on “Immunoreceptors” took place at the base of Mount Werner in the area of Steamboat Springs, Colorado in June, 2014. At this splendid location, the diversity in structures, dynamics and characteristics of receptors in the immune system were discussed, including integrins, T and B cell receptors, and Fc receptors (FcR). Part of the meeting focused on therapeutic applications and their mechanisms of actions. The FASEB SRCs on immunoreceptors started in the early 1990s and succeeded again in providing a highly interactive setting for participating junior and senior scientists. As in former meetings (1), the organizers put together a scientific program encompassing many recent advances in the field of immunoreceptors. In this report, we highlight some of the exciting topics that were presented during this 5-day meeting. Keynote speaker Timothy Springer (Harvard University, Boston, MA, USA) kicked off the scientific part of the meeting by providing a historical overview of the integrin field, in particular, lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), and their role in diapedesis. The process of achieving full integrin activation attained after establishing the “extended open” conformation was discussed in more detail, requiring both cytoskeletal mediated pulling forces and ligand engagement 740
(2). He also showed new insights on LFA-1 structure from electron microscopy studies aimed to unravel the conformational changes upon interaction with ligands (ICAM-1, CD11d, iC3b) or antibody F(ab) fragments. EVOLUTION, STRUCTURE, AND ANTIGEN INTERACTIONS OF IMMUNORECEPTORS Our adaptive immune system is able to generate a plethora of antigen-recognition specificities driven by somatic hypermutation and gene reorganization. The textbook example of this is the random rearrangement of the V(D)J gene segments, the building blocks for antibodies and T cell receptors (TCRs) produced by B and T cells. Sharks, being one of the oldest vertebrates expressing major histocompatibility complex (MHC), Ig, and TCRs, provide an intriguing model system to understand the mechanism behind antigen-recognition diversity. Martin Flajnik (University of Maryland, Baltimore, MD, USA) studies the 1
Correspondence: UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail: j.h.w.leusen@ umcutrecht.nl doi: 10.1096/fj.15-0302ufm
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development of the shark-specific Ig isotype IgNAR, homodimeric heavy chain-only antibodies (HCAbs) similar to the single domain antibodies found in camelids. These HCAbs complement the conventional heavy and light chain-containing antibodies and pose an interesting question on why HCAbs are not more widespread in evolution (3). Lamprey, belonging to the class of jawless vertebrates or Agnathostomata, expresses another antibodylike molecule referred to as the variable lymphocyte receptor (VLR) (4). These VLRs are the counterparts of immunoglobulin-based receptors used for antigen recognition as discussed by Brantly Herrin (Emory Uiversity, Atlanta, GA, USA). The development of monoclonal VLRB antibodies and VLR-IgG(Fc) chimeras illustrates the possible therapeutic potential that can be gained from investigating such ancient species. A distinct lineage of T cells, the gd T cells, are well equipped to recognize dysregulated cells. The laboratory of Erin Adams (University of Chicago, Chicago, IL, USA) has been investigating the antigen recognition of the gd TCRs, in particular, the Vg9Vd2 T cells, which are present at relatively high numbers in the blood. Vg9Vd2 T cells are activated by cells that generate phosphoantigens (pAgs), a pathway often up-regulated in malignant or infected cells. The BTN3A1 protein on target cells is crucial here; it senses the intracellular concentration of pAgs through its direct interaction with a positively charged pocket within the cytosolic domain of BTN3A1. How the Vg9Vd2 TCR then interacts with the pAg-bound form of BTN3A remains to be solved (5). Jamie Rossjohn (Monash University, Melbourne, VIC, Australia) talked about their recent structural work on mucosal-associated invariant T cell (MAIT) receptor and its recognition of a MHC-related molecule, MR1. It is noteworthy that his group showed that MR1 bind microbial-based vitamin B precursors, raising the possibility of MAIT TCR recognition of microbial pathogens (6). Cheng Zhu (Georgia Institute of Technology, Atlanta, GA, USA) focuses on the physical forces that are involved during TCR engagement to address the function of TCRs as a mechanosensor. While applying force by using an atomic force microscope-like system, the lifetimes of single agonistic or antagonistic TCR-pMHC bonds can be measured. His findings support a model where the magnitude, duration, frequency, and timing of the force on the TCR determine its signaling capacity (7). TCR ANTIGEN RECOGNITION AND SPECIFICITIES The peptide-loaded MHC (pMHC) interaction with abTCR has been studied extensively for its fundamental features of thymic selection and T cell activation. A currently debated issue is the origin of TCR specificity for pMHC. Whereas the structural work from Christopher Garcia’s (Stanford University, Palo Alto, CA, USA) group on murine Vb8 family of TCRs has led to a germline hypothesis (8), recent work from Singer’s group supports the previously established model of thymic selection (9). To further debate this fundamental issue of immunology, a session titled “T cell receptor antigen recognition and specificities” took place with speakers on both views of TCR selection. Alfred Singer [National Institutes of Health (NIH), Bethesda, MD, USA] discussed the process of MEETING REPORT ON IMMUNORECEPTORS 2014
thymic selection, which requires CD4/CD8-directed sequestration of the signaling protein tyrosine kinase Lck to generate T cells expressing abT cell antigen receptors. By use of mice deficient in the CD4/CD8 coreceptors, it was found that the thymus can select MHC-independent abTCR, which instead recognizes other molecules, such as CD155 (10). The role of coreceptors in TCR signaling was further elaborated by Roy Mariuzza’s (University of Maryland) structural work on CD4/TCR/MHC complex. Garcia discussed their TCR structural footprint on various MHC complexes that resulted in potentially geometrical restrain in TCR activation (11). It is clear that TCRs react with peptides bound to MHC, but the involvement of the direct interaction between TCRs and MHC itself and its relation to positive selection in the thymus is less clear. John Kappler (National Jewish Health, Denver, CO, USA) discussed this issue and investigates whether an intrinsic reactivity between the two could be based on conserved motifs within the TCR. He offered the audience a persuasive lecture proposing that evolutionary predispositions within the TCR CDR2 domains are present, which are important for engaging MHC. An example of this is the presence of a tyrosine motif (Tyr46,Tyr48) in the family of mouse TCR Vb8 chains that adopt similar positions and configurations when binding MHCI or MHCII (12). It was suggested that other patterns of amino acids contained within the TCR variable elements function in a similar way. Intimately related to this subject is the work of Philippa Marrack (NJH, USA) who focuses on the TCR features that determine MHC allele recognition. By use of mice that express different MHCII alleles and a single TCR b chain, a comparison was made between the a chain sequences that are found on na¨ıve CD4 T cells. Rather unexpected, the major differences appeared in the CD3 sequences, a region normally regarded as mainly interacting with the MHC-bound peptide. The idea that MHC-bound peptides might dictate the allele specificity of positive selection rather than MHCII itself and other unresolved issues fueled some intense discussions during this session. PENTRAXINS AND FCR The 2014 Conference included for the first time a session on “Pentraxins and Fc Receptors” to explore a recently emerged area of the biology of pentraxins and their involvement in infection and inflammation through FcR activations. To this end, Terry Du Clos (University of New Mexico, Albuquerque, NM, USA) reviewed the current knowledge of pentraxins, including C-reactive protein (CRP) and serum amyloid P component (SAP), and others (13). He then spoke about a newly discovered function of CRP in activating dendritic cells (DC) to induce Th17 differentiation. Heat-aggregated CRP activated Fcg receptors (FcgR) on DC, resulting in the production of Th17 differentiation cytokines interleukin (IL)-1b, IL-6, tumor necrosis factor-a, and IL-23. Further co-culture with helper T cells resulted in secretion of IL-17 and IFN-g. A clinical study led by Sonlee West (University of New Mexico) found an increased risk of sepsis in trauma patients expressing the allelic form of FcgRIIa (His131 variant) that binds CRP poorly. CRP was able to protect monocytes from deactivation in vitro, but only when the Arg131 741
variant of FcgRIIa was expressed. Alexander J. Szalai (University of Alabama Birmingham, Birmingham, AL, USA) reviewed work performed by his laboratory using mice that are either transgenic for human CRP or genetically deficient in mouse CRP. He described several disease models where these genetic manipulations had dramatic effects that required certain FcgR. The impact of CRP is disease specific with either exacerbation (cardiovascular disease) (14) or amelioration (autoimmune encephalomyelitis) (15) affected by CRP. In addition, there are different roles for activating or inhibitory FcgR depending on the model. Peter Sun (NIH) reported recent findings of pentraxin binding to FcaRI (CD89) and showed through mutational analysis that CRP and IgA share a binding site on FcaRI. He also introduced another acute phase protein, serum amyloid A (SAA), and described structural and functional studies of SAA in inflammation, especially in inflammatory amyloidosis (16). Structural studies identified a secluded region of SAA in its native hexameric form as the amyloidogenic segment. Use of electron microscopy imaging and deletion constructs also identified the C-terminal tail as a critical switch to initiate SAA amyloidosis. The physiological role of SAA is unknown. Darrell Pilling (Texas A&M University, College Station, TX, USA) spoke about the role of SAP, another member of the pentraxin family, in regulation of inflammation and fibrosis using animal models. Mice deficient in SAP showed increased fibrosis, and injections of exogenous SAP reduced inflammation and prevented fibrosis. In addition, it was shown that distinct FcgR mediate the effect of SAP on neutrophil adhesion and fibrocyte differentiation (17). Scott Reed (University of Colorado Denver, Denver, CO, USA) presented data on the effects of lipid membrane structure on CRP ligand binding, which are significant for understanding CRP binding to low-density lipoproteins (18). Mark Davis (Stanford University) spoke about TCR repertoire and functionality in vaccination and diseases in the session titled “Regulation of Response”. By using highly antigen-specific MHC-tetramer staining, he showed that many TCRs are cross-reactive and that vaccination against one pathogen may offer protection against many different pathogens. This could explain the phenomenon his group has found in which adults have large numbers of memory phenotype T cells for pathogens that they have never encountered (19). IMMUNORECEPTORS AND SIGNALING Collateral damage of healthy tissue at pathogen exposed areas is partly controlled by inhibiting immune cell activation and influx from the blood. Inhibitory receptors expressed by immune cells play an important role in controlling inflammation. In this context, Paul Crocker (University of Dundee, Dundee, Scotland, United Kingdom) looked at the sialic acid-binding Ig-like lectin E (Siglec-E) expressed on murine myeloid cells. It was demonstrated before that Siglec-E inhibits b2-integrin dependent neutrophil recruitment after LPS exposure. Further research now shows that sialic acid-dependent Siglec-E signaling promotes CD11b integrin induced ROS production by neutrophils, probably mediated via Akt activation. Therefore, it is proposed that the interaction of host glycans with 742
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Siglec-E has immune inhibitory effects caused by its stimulation of ROS production, ultimately suppressing neutrophil recruitment (20). Linde Meyaard (University Medical center Utrecht, Utrecht, The Netherlands) reminded the audience of the fact that ;100 immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors have been identified and that knockout studies show a profound susceptibility for autoimmunity (21). Neutrophils are implicated in autoimmune settings through formation of neutrophil extracellular traps (NETs) that do not only mediate pathogen clearance but can also cause endothelial damage and aggravation of autoimmune disease. In more detail, Meyaard is studying the inhibitory receptor systemic lupus erythematosus (SIRL-1), which is highly expressed on human neutrophils and monocytes (22). Antibody-mediated ligation of SIRL-1 inhibits SLE-related NET release (23). These data indicate that immune inhibitory receptors such as SIRL-1 might be attractive targets for future treatments of autoimmune diseases. Juan Rivera (NIH) is well known for his work on the Fc«RI, the receptor for IgE, mainly expressed on mast cells (MC) and basophils. His most recent work has focused on whether the Fc«RI is able to distinguish high- versus lowaffinity antigen recognition by IgE. A clear difference was observed regarding degranulation, cytokine, and chemokine responses when using high- or low-affinity antigen. However, the kinetics of Fc«RI phosphorylation were the same, albeit that 100-fold more of the low-affinity antigen is needed compared with the high-affinity antigen. Studying Fc«RI clustering using total internal reflection fluorescence (TIRF) microscopy revealed that there is an effect on cluster number, mobility, and organization within the synapse depending on the affinity to the antigen. The manner of Fc«RI phosphorylation did differ, leading to a change in the balance between phosphorylated LAT1 and LAT2. The cause for the differential Fc«RI phosphorylation was attributed to an increased recruitment of the Src kinase Fgr to Fc«RI, induced in the presence of the low-affinity antigen and leading to a relative increase in LAT2 phosphorylation. Thus, antigen affinity-dependent clustering of the Fc«RI determines the balance in receptor-associated kinases and subsequent downstream signaling. Further, in vivo challenge with high- or low-affinity antigen results in differences in effector cell recruitment and cytokine profiles (24). Ongoing work concerns the role of autoreactive IgE and dysregulation of IgE production and the therapeutic potential of anti-IgE (omalizumab) in relation to autoimmunity. Diane Lidke (University of New Mexico) is a specialist on Fc«RI behavior in living cells. Recently, she investigated the dynamics of Fc«RI in the MC synapse using life cell imaging and monovalent dinitrophenol (DNP)-decorated bilayers. Life recruitment of Fc«RI and Syk kinase to the synapse was visualized and revealed that Syk binding does not depend on receptor cluster size and is transient, indicating that Fc«RIcontacted Syk is readily available to facilitate downstream interaction with LAT. Further imaging experiments of the MCdendritic cell (DC) synapse suggest that fluorescently labeled IgE immune complexes (IgE-ICs) are internalized at the synapse. The presence of IgE-ICs prolonged the MC-DC interaction, during which LFA-1- and VLA-4-dependent endosome polarization was observed. In addition, transfer of immune complexes towards the DC was observed. The manner of transfer remains unsolved but a possible function might be to feed the antigen presentation pathway of the DC.
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Immune cells rely on the activation and collaboration of multiple different receptors in the plasma membrane that are central to leukocyte function. In this context, Annemiek van Spriel (Radboud UMC) discussed the importance of tetraspanin proteins (CD37, CD53) in controlling immunoreceptor organization in the plasma membrane. In B lymphocytes, the tetraspanin CD37 is required for the mobility and clustering of a4b1-integrin (VLA-4) molecules at the cell surface, which is important for plasma cell survival and antibody production in vivo (25). Moreover, tetraspanins can facilitate membrane-proximal signal transduction by their ability to recruit certain signaling molecules (protein kinase C) to the plasma membrane. NK cells are famous for polarized degranulation to destroy their specifically recognized target, a topic investigated by Eric Long (NIH). In NK cells, signals for granule polarization and degranulation are uncoupled, and integrin LFA-1 signaling is sufficient to trigger polarization but not degranulation (26). By use of an elegant proteomics approach with ICAM-1-bearing insect cells as targets and pulldown with anti-p-Tyr (4G10), new LFA-1induced downstream signaling molecules were identified and tested functionally for their role in granule polarization, including ILK (integrin-linked kinase), paxillin, and Pyk2. This ILK signaling network was coupled to a downstream Cdc42-dependent pathway that was also required for granule polarization. Long elaborated mostly on ILK whose involvement was verified by performing proximity ligation assays (duo-link), indicating that ILK-CD18 interaction is induced by ICAM-1. LFA-1 signaling through ILK is sufficient for granule convergence to the microtubuleorganizing center (MTOC) and for polarization of MTOC towards the target cell (27). THERAPEUTIC APPLICATIONS INVOLVING IMMUNORECEPTORS Monoclonal antibody (mAb) therapy is a successful and important treatment for patients with malignancies and autoimmune diseases. All U.S. Food and Drug Administration-approved mAbs are of the IgG class. Jeanette Leusen (University Medical Center Utrecht) explores IgA as a novel type of antibody for treatment of cancer. In most mouse models, she showed that IgA antibodies targeting epidermal growth factor receptor critically depend on the FcR for IgA (FcaRI) for their mode of action. In vitro, polymorphonuclear cells (PMN) are the most important effector cells to kill IgA-opsonized tumor cells, but the exact mechanism is yet unknown. Life imaging of neutrophils killing antibody-opsonized target cells suggest that PMN “eat” parts of tumor cells until they die. Toine ten Broeke from the group of Dr. Leusen showed data that when IgA and IgG antibodies are combined, they can act synergistically through the combination of effector cells. One of the challenges of IgA therapy is the relative short half-life of IgA, especially in mice. Targeting of IgA to the neonatal FcR (FcRn) might overcome this. The FcRn is also the interest of Sally Ward (University of Texas Southwestern Medical Center, Dallas, TX, USA). This receptor is ubiquitously expressed and salvages IgG from lysosomal degradation by pH-dependent binding of IgG in the endocytic system, sorting into tubulovesicular MEETING REPORT ON IMMUNORECEPTORS 2014
transport carriers, and return to the cell surface where it is released into the extracellular space. In the clinic, mAbs directed against soluble factors (e.g. cytokines) are used. Efficacy of such therapies can, however, be hampered by FcRn-mediated redirection of mAb-targeted molecules into the recycling pathway, resulting in an “antibodybuffering” effect that increases the persistence of target molecules. Ward has been engineering mAbs that release their target at endosomal pH, thereby circumventing this problem. Alternative ways to inhibit FcRn function by devising mAbs that bind more strongly to FcRn, and are less pH dependent, are also part of this research. An elegant example of this was presented for a more diagnostic setting (positron emission tomography scan) where relatively fast clearance of circulating background radiolabeled mAb following tumor loading is achieved in mice by using FcRn inhibitors or “Abdegs” (28). Mark Hogarth (Burnet Institute, Melbourne, VIC, Australia) has a long track record regarding FcR biology. Preclinical evaluation of vaccines and therapeutic antibodies are often performed in macaques, and in this context, Hogarth looked at interspecies differences in IgG-FcgR interaction. In more detail, it is found that the binding characteristics of human IgG subclasses to the Macaca nemestrina FcgRs can differ profoundly. Further, FcgR expression can vary as illustrated by the observation that FcgRIII is absent, whereas FcgRII is elevated on M. nemestrina neutrophils in comparison to human (29). Considering these studies, Hogarth advocates cautious interpretation of Ab-induced responses in monkeys, and verification in other animal systems is required. Autoimmune disease can be treated by intravenous administration of intravenous immunoglobulin G (IVIG). According to Falk Nimmerjahn (University of ErlangenNuernberg, Erlangen, Germany), the mechanism behind IVIG treatment partly depends on Fc-mediated effects through interaction with the inhibitory FcgRIIB, and on the extent of Fc sialylation. Mouse models using highly pure mono- or disialylated IgG glycoforms have an enhanced activity, and IVIG may restore immune homeostasis by normalizing serum IgG sialylation. Experiments with human bone marrow reconstituted mice have verified the requirement of sialylation for IVIG activity (30). The apparent role of sialylation also supports the involvement of C-type lectin receptors (DC-SIGN, CD22) that upon blockage can modulate IVIG activity in mouse models. REFERENCES 1. Leusen, J. H. W. (2012) Immunoreceptors: Evolution, structure and therapeutic applications. EMBO Rep. 13, 1046–1048 2. Springer, T. A., and Dustin, M. L. (2012) Integrin inside-out signaling and the immunological synapse. Curr. Opin. Cell Biol. 24, 107–115 3. Flajnik, M. F., Deschacht, N., and Muyldermans, S. (2011) A case of convergence: Why did a simple alternative to canonical antibodies arise in sharks and camels? PLoS Biol. 9, e1001120 4. Herrin, B. R., and Cooper, M. D. (2010) Alternative adaptive immunity in jawless vertebrates. J. Immunol. 185, 1367–1374 5. Sandstrom, A., Peign´e, C. M., L´eger, A., Crooks, J. E., Konczak, F., Gesnel, M. C., Breathnach, R., Bonneville, M., Scotet, E., and Adams, E. J. (2014) The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vg9Vd2 T cells. Immunity 40, 490–500 6. Kjer-Nielsen, L., Patel, O., Corbett, A. J., Le Nours, J., Meehan, B., Liu, L., et al. (2012) vMR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723
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7. Liu, B., Chen, W., Evavold, B., and Zhu, C. (2014) Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell 157, 357–368 8. Garcia, C. K., Adams, J. J., Feng, D., and Ely, L. K. (2009) The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat. Immunol. 10, 143–147 9. Van Laethem, F., Sarafova, S. D., Park, J., Tai, X., Pobezinsky, L., Guinter, T., Adoro, S., Adams, A., Sharrow, S. O., Feigenbaum, L., and Singer, A. (2007) Deletion of CD4 and CD8 coreceptors permits generation of abT cells that recognize antigens independently of the MHC. Immunity 27, 735–750 10. Van Laethem, F., Tikhonova, A., Pobezinsky, L., Tai, X., Kimura, M., Le Saout, C., et al. (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154, 1326–1341 11. Birnbaum, M., Mendoza, J., Sethi, D., Dong, S., Glanville, J., Dobbins, J., et al. (2014) Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157, 1073–1087 12. Yin, L., Scott-Browne, J., Kappler, J. W., Gapin, L., and Marrack, P. (2012) T cells and their eons-old obsession with MHC. Immunol. Rev. 250, 49–60 13. Lu, J., Marjon, K. D., Mold, C., Du Clos, T. W., and Sun, P. D. (2012) Pentraxins and Fc receptors. Immunol. Rev. 250, 230–238 14. Szalai, A. J., McCrory, M. A., Xing, D., Hage, F. G., Miller, A., Oparil, S., Chen, Y. F., Mazzone, M., Early, R., Henry, S. P., Zanardi, T. A., Graham, M. J., and Crooke, R. M. (2014) Inhibiting C-reactive protein for the treatment of cardiovascular disease: Promising evidence from rodent models. Mediators Inflamm. 2014, 353614 15. Hu, X.-Z., Wright, T. T., Jones, N. R., Ramos, T. N., Skibinski, G. A., McCrory, M. A., Barnum, S. R., and Szalai, A. J. (2011) Inhibition of experimental autoimmune encephalomyelitis in human C-reactive protein transgenic mice is FcgammaRIIB dependent. Autoimmune Dis. DOI: 10.4061/2011/484936 16. Lu, J., Yu, Y., Zhu, I., Cheng, Y., and Sun, P. D. (2014) Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis. Proc. Natl. Acad. Sci. USA 111, 5189–5194 17. Cox, N., Pilling, D., and Gomer, R. H. (2014) Distinct Fcg receptors mediate the effect of serum amyloid p on neutrophil adhesion and fibrocyte differentiation. J. Immunol. 193, 1701–1708 18. Wang, M. S., Messersmith, R. E., and Reed, S. M. (2012) Membrane curvature recognition by C-reactive protein using lipoprotein mimics. Soft Matter 8, 7909–7918 19. Su, L., Kidd, B., Han, A., Kotzin, J., and Davis, M. (2013) Virusspecific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–383
20. McMillan, S. J., Sharma, R. S., Richards, H. E., Hegde, V., and Crocker, P. R. (2014) Siglec-E promotes b2-integrin-dependent NADPH oxidase activation to suppress neutrophil recruitment to the lung. J. Biol. Chem. 289, 20370–20376 21. Olde Nordkamp, M. J. M., Koeleman, B. P., and Meyaard, L. (2014) Do inhibitory immune receptors play a role in the etiology of autoimmune disease? Clin. Immunol. 150, 31–42 22. Steevels, T. A. M., Lebbink, R. J., Westerlaken, G. H. A., Coffer, P. J., and Meyaard, L. (2010) Signal inhibitory receptor on leukocytes-1 is a novel functional inhibitory immune receptor expressed on human phagocytes. J. Immunol. 184, 4741–4748 23. Van Avondt, K., Fritsch-Stork, R., Derksen, R. H. W. M., and Meyaard, L. (2013) Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus. PLoS ONE 8, e78459 24. Suzuki, R., Leach, S., Liu, W., Ralston, E., Scheffel, J., Zhang, W., Lowell, C. A., and Rivera, J. (2014) Molecular editing of cellular responses by the high-affinity receptor for IgE. Science 343, 1021–1025 25. van Spriel, A. B., de Keijzer, S., van der Schaaf, A., Gartlan, K. H., Sofi, M., Light, A., Linssen, P. C., Boezeman, J. B., Zuidscherwoude, M., Reinieren-Beeren, I., Cambi, A., Mackay, F., Tarlinton, D. M., Figdor, C. G., and Wright, M. D. (2012) The tetraspanin CD37 orchestrates the a(4)b(1) integrin-Akt signaling axis and supports long-lived plasma cell survival. Sci. Signal. 5, ra82 26. Bryceson, Y. T., March, M. E., Barber, D. F., Ljunggren, H. G., and Long, E. O. (2005) Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J. Exp. Med. 202, 1001–1012 27. Zhang, M., March, M., Lane, W., and Long, E. (2014) A signaling network stimulated by beta2 integrin promotes the polarization of lytic granules in cytotoxic cells. Sci. Signal. 7, ra96 28. Ward, E. S., Velmurugan, R., and Ober, R. J. (2014) Targeting FcRn for therapy: From live cell imaging to in vivo studies in mice. Immunol. Lett. 160, 158–162 29. Trist, H. M., Tan, P. S., Wines, B. D., Ramsland, P. A., Orlowski, E., Stubbs, J., Gardiner, E. E., Pietersz, G. A., Kent, S. J., Stratov, I., Burton, D. R., and Hogarth, P. M. (2014) Polymorphisms and interspecies differences of the activating and inhibitory FcgRII of Macaca nemestrina influence the binding of human IgG subclasses. J. Immunol. 192, 792–803 30. Schwab, I., Mihai, S., Seeling, M., Kasperkiewicz, M., Ludwig, R. J., and Nimmerjahn, F. (2014) Broad requirement for terminal sialic acid residues and FcgRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur. J. Immunol. 44, 1444–1453
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Meeting Report on Immunoreceptors 2014 Toine ten Broeke,* Annemiek van Spriel,† Peter Sun,‡ and Jeanette Leusen*,1 *Laboratory of Translational Immunology, Immunotherapy Group, University Medical Center Utrecht, Utrecht, The Netherlands; †Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; and ‡Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Attendees of the FASEB Science Research Conference: Immunoreceptors (June 15–20, 2014) in Steamboat Springs, CO, USA.
THE 2014 FASEB SCIENCE Research Conference (SRC) on “Immunoreceptors” took place at the base of Mount Werner in the area of Steamboat Springs, Colorado in June, 2014. At this splendid location, the diversity in structures, dynamics and characteristics of receptors in the immune system were discussed, including integrins, T and B cell receptors, and Fc receptors (FcR). Part of the meeting focused on therapeutic applications and their mechanisms of actions. The FASEB SRCs on immunoreceptors started in the early 1990s and succeeded again in providing a highly interactive setting for participating junior and senior scientists. As in former meetings (1), the organizers put together a scientific program encompassing many recent advances in the field of immunoreceptors. In this report, we highlight some of the exciting topics that were presented during this 5-day meeting. Keynote speaker Timothy Springer (Harvard University, Boston, MA, USA) kicked off the scientific part of the meeting by providing a historical overview of the integrin field, in particular, lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), and their role in diapedesis. The process of achieving full integrin activation attained after establishing the “extended open” conformation was discussed in more detail, requiring both cytoskeletal mediated pulling forces and ligand engagement 740
(2). He also showed new insights on LFA-1 structure from electron microscopy studies aimed to unravel the conformational changes upon interaction with ligands (ICAM-1, CD11d, iC3b) or antibody F(ab) fragments. EVOLUTION, STRUCTURE, AND ANTIGEN INTERACTIONS OF IMMUNORECEPTORS Our adaptive immune system is able to generate a plethora of antigen-recognition specificities driven by somatic hypermutation and gene reorganization. The textbook example of this is the random rearrangement of the V(D)J gene segments, the building blocks for antibodies and T cell receptors (TCRs) produced by B and T cells. Sharks, being one of the oldest vertebrates expressing major histocompatibility complex (MHC), Ig, and TCRs, provide an intriguing model system to understand the mechanism behind antigen-recognition diversity. Martin Flajnik (University of Maryland, Baltimore, MD, USA) studies the 1
Correspondence: UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail: j.h.w.leusen@ umcutrecht.nl doi: 10.1096/fj.15-0302ufm
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development of the shark-specific Ig isotype IgNAR, homodimeric heavy chain-only antibodies (HCAbs) similar to the single domain antibodies found in camelids. These HCAbs complement the conventional heavy and light chain-containing antibodies and pose an interesting question on why HCAbs are not more widespread in evolution (3). Lamprey, belonging to the class of jawless vertebrates or Agnathostomata, expresses another antibodylike molecule referred to as the variable lymphocyte receptor (VLR) (4). These VLRs are the counterparts of immunoglobulin-based receptors used for antigen recognition as discussed by Brantly Herrin (Emory Uiversity, Atlanta, GA, USA). The development of monoclonal VLRB antibodies and VLR-IgG(Fc) chimeras illustrates the possible therapeutic potential that can be gained from investigating such ancient species. A distinct lineage of T cells, the gd T cells, are well equipped to recognize dysregulated cells. The laboratory of Erin Adams (University of Chicago, Chicago, IL, USA) has been investigating the antigen recognition of the gd TCRs, in particular, the Vg9Vd2 T cells, which are present at relatively high numbers in the blood. Vg9Vd2 T cells are activated by cells that generate phosphoantigens (pAgs), a pathway often up-regulated in malignant or infected cells. The BTN3A1 protein on target cells is crucial here; it senses the intracellular concentration of pAgs through its direct interaction with a positively charged pocket within the cytosolic domain of BTN3A1. How the Vg9Vd2 TCR then interacts with the pAg-bound form of BTN3A remains to be solved (5). Jamie Rossjohn (Monash University, Melbourne, VIC, Australia) talked about their recent structural work on mucosal-associated invariant T cell (MAIT) receptor and its recognition of a MHC-related molecule, MR1. It is noteworthy that his group showed that MR1 bind microbial-based vitamin B precursors, raising the possibility of MAIT TCR recognition of microbial pathogens (6). Cheng Zhu (Georgia Institute of Technology, Atlanta, GA, USA) focuses on the physical forces that are involved during TCR engagement to address the function of TCRs as a mechanosensor. While applying force by using an atomic force microscope-like system, the lifetimes of single agonistic or antagonistic TCR-pMHC bonds can be measured. His findings support a model where the magnitude, duration, frequency, and timing of the force on the TCR determine its signaling capacity (7). TCR ANTIGEN RECOGNITION AND SPECIFICITIES The peptide-loaded MHC (pMHC) interaction with abTCR has been studied extensively for its fundamental features of thymic selection and T cell activation. A currently debated issue is the origin of TCR specificity for pMHC. Whereas the structural work from Christopher Garcia’s (Stanford University, Palo Alto, CA, USA) group on murine Vb8 family of TCRs has led to a germline hypothesis (8), recent work from Singer’s group supports the previously established model of thymic selection (9). To further debate this fundamental issue of immunology, a session titled “T cell receptor antigen recognition and specificities” took place with speakers on both views of TCR selection. Alfred Singer [National Institutes of Health (NIH), Bethesda, MD, USA] discussed the process of MEETING REPORT ON IMMUNORECEPTORS 2014
thymic selection, which requires CD4/CD8-directed sequestration of the signaling protein tyrosine kinase Lck to generate T cells expressing abT cell antigen receptors. By use of mice deficient in the CD4/CD8 coreceptors, it was found that the thymus can select MHC-independent abTCR, which instead recognizes other molecules, such as CD155 (10). The role of coreceptors in TCR signaling was further elaborated by Roy Mariuzza’s (University of Maryland) structural work on CD4/TCR/MHC complex. Garcia discussed their TCR structural footprint on various MHC complexes that resulted in potentially geometrical restrain in TCR activation (11). It is clear that TCRs react with peptides bound to MHC, but the involvement of the direct interaction between TCRs and MHC itself and its relation to positive selection in the thymus is less clear. John Kappler (National Jewish Health, Denver, CO, USA) discussed this issue and investigates whether an intrinsic reactivity between the two could be based on conserved motifs within the TCR. He offered the audience a persuasive lecture proposing that evolutionary predispositions within the TCR CDR2 domains are present, which are important for engaging MHC. An example of this is the presence of a tyrosine motif (Tyr46,Tyr48) in the family of mouse TCR Vb8 chains that adopt similar positions and configurations when binding MHCI or MHCII (12). It was suggested that other patterns of amino acids contained within the TCR variable elements function in a similar way. Intimately related to this subject is the work of Philippa Marrack (NJH, USA) who focuses on the TCR features that determine MHC allele recognition. By use of mice that express different MHCII alleles and a single TCR b chain, a comparison was made between the a chain sequences that are found on na¨ıve CD4 T cells. Rather unexpected, the major differences appeared in the CD3 sequences, a region normally regarded as mainly interacting with the MHC-bound peptide. The idea that MHC-bound peptides might dictate the allele specificity of positive selection rather than MHCII itself and other unresolved issues fueled some intense discussions during this session. PENTRAXINS AND FCR The 2014 Conference included for the first time a session on “Pentraxins and Fc Receptors” to explore a recently emerged area of the biology of pentraxins and their involvement in infection and inflammation through FcR activations. To this end, Terry Du Clos (University of New Mexico, Albuquerque, NM, USA) reviewed the current knowledge of pentraxins, including C-reactive protein (CRP) and serum amyloid P component (SAP), and others (13). He then spoke about a newly discovered function of CRP in activating dendritic cells (DC) to induce Th17 differentiation. Heat-aggregated CRP activated Fcg receptors (FcgR) on DC, resulting in the production of Th17 differentiation cytokines interleukin (IL)-1b, IL-6, tumor necrosis factor-a, and IL-23. Further co-culture with helper T cells resulted in secretion of IL-17 and IFN-g. A clinical study led by Sonlee West (University of New Mexico) found an increased risk of sepsis in trauma patients expressing the allelic form of FcgRIIa (His131 variant) that binds CRP poorly. CRP was able to protect monocytes from deactivation in vitro, but only when the Arg131 741
variant of FcgRIIa was expressed. Alexander J. Szalai (University of Alabama Birmingham, Birmingham, AL, USA) reviewed work performed by his laboratory using mice that are either transgenic for human CRP or genetically deficient in mouse CRP. He described several disease models where these genetic manipulations had dramatic effects that required certain FcgR. The impact of CRP is disease specific with either exacerbation (cardiovascular disease) (14) or amelioration (autoimmune encephalomyelitis) (15) affected by CRP. In addition, there are different roles for activating or inhibitory FcgR depending on the model. Peter Sun (NIH) reported recent findings of pentraxin binding to FcaRI (CD89) and showed through mutational analysis that CRP and IgA share a binding site on FcaRI. He also introduced another acute phase protein, serum amyloid A (SAA), and described structural and functional studies of SAA in inflammation, especially in inflammatory amyloidosis (16). Structural studies identified a secluded region of SAA in its native hexameric form as the amyloidogenic segment. Use of electron microscopy imaging and deletion constructs also identified the C-terminal tail as a critical switch to initiate SAA amyloidosis. The physiological role of SAA is unknown. Darrell Pilling (Texas A&M University, College Station, TX, USA) spoke about the role of SAP, another member of the pentraxin family, in regulation of inflammation and fibrosis using animal models. Mice deficient in SAP showed increased fibrosis, and injections of exogenous SAP reduced inflammation and prevented fibrosis. In addition, it was shown that distinct FcgR mediate the effect of SAP on neutrophil adhesion and fibrocyte differentiation (17). Scott Reed (University of Colorado Denver, Denver, CO, USA) presented data on the effects of lipid membrane structure on CRP ligand binding, which are significant for understanding CRP binding to low-density lipoproteins (18). Mark Davis (Stanford University) spoke about TCR repertoire and functionality in vaccination and diseases in the session titled “Regulation of Response”. By using highly antigen-specific MHC-tetramer staining, he showed that many TCRs are cross-reactive and that vaccination against one pathogen may offer protection against many different pathogens. This could explain the phenomenon his group has found in which adults have large numbers of memory phenotype T cells for pathogens that they have never encountered (19). IMMUNORECEPTORS AND SIGNALING Collateral damage of healthy tissue at pathogen exposed areas is partly controlled by inhibiting immune cell activation and influx from the blood. Inhibitory receptors expressed by immune cells play an important role in controlling inflammation. In this context, Paul Crocker (University of Dundee, Dundee, Scotland, United Kingdom) looked at the sialic acid-binding Ig-like lectin E (Siglec-E) expressed on murine myeloid cells. It was demonstrated before that Siglec-E inhibits b2-integrin dependent neutrophil recruitment after LPS exposure. Further research now shows that sialic acid-dependent Siglec-E signaling promotes CD11b integrin induced ROS production by neutrophils, probably mediated via Akt activation. Therefore, it is proposed that the interaction of host glycans with 742
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Siglec-E has immune inhibitory effects caused by its stimulation of ROS production, ultimately suppressing neutrophil recruitment (20). Linde Meyaard (University Medical center Utrecht, Utrecht, The Netherlands) reminded the audience of the fact that ;100 immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors have been identified and that knockout studies show a profound susceptibility for autoimmunity (21). Neutrophils are implicated in autoimmune settings through formation of neutrophil extracellular traps (NETs) that do not only mediate pathogen clearance but can also cause endothelial damage and aggravation of autoimmune disease. In more detail, Meyaard is studying the inhibitory receptor systemic lupus erythematosus (SIRL-1), which is highly expressed on human neutrophils and monocytes (22). Antibody-mediated ligation of SIRL-1 inhibits SLE-related NET release (23). These data indicate that immune inhibitory receptors such as SIRL-1 might be attractive targets for future treatments of autoimmune diseases. Juan Rivera (NIH) is well known for his work on the Fc«RI, the receptor for IgE, mainly expressed on mast cells (MC) and basophils. His most recent work has focused on whether the Fc«RI is able to distinguish high- versus lowaffinity antigen recognition by IgE. A clear difference was observed regarding degranulation, cytokine, and chemokine responses when using high- or low-affinity antigen. However, the kinetics of Fc«RI phosphorylation were the same, albeit that 100-fold more of the low-affinity antigen is needed compared with the high-affinity antigen. Studying Fc«RI clustering using total internal reflection fluorescence (TIRF) microscopy revealed that there is an effect on cluster number, mobility, and organization within the synapse depending on the affinity to the antigen. The manner of Fc«RI phosphorylation did differ, leading to a change in the balance between phosphorylated LAT1 and LAT2. The cause for the differential Fc«RI phosphorylation was attributed to an increased recruitment of the Src kinase Fgr to Fc«RI, induced in the presence of the low-affinity antigen and leading to a relative increase in LAT2 phosphorylation. Thus, antigen affinity-dependent clustering of the Fc«RI determines the balance in receptor-associated kinases and subsequent downstream signaling. Further, in vivo challenge with high- or low-affinity antigen results in differences in effector cell recruitment and cytokine profiles (24). Ongoing work concerns the role of autoreactive IgE and dysregulation of IgE production and the therapeutic potential of anti-IgE (omalizumab) in relation to autoimmunity. Diane Lidke (University of New Mexico) is a specialist on Fc«RI behavior in living cells. Recently, she investigated the dynamics of Fc«RI in the MC synapse using life cell imaging and monovalent dinitrophenol (DNP)-decorated bilayers. Life recruitment of Fc«RI and Syk kinase to the synapse was visualized and revealed that Syk binding does not depend on receptor cluster size and is transient, indicating that Fc«RIcontacted Syk is readily available to facilitate downstream interaction with LAT. Further imaging experiments of the MCdendritic cell (DC) synapse suggest that fluorescently labeled IgE immune complexes (IgE-ICs) are internalized at the synapse. The presence of IgE-ICs prolonged the MC-DC interaction, during which LFA-1- and VLA-4-dependent endosome polarization was observed. In addition, transfer of immune complexes towards the DC was observed. The manner of transfer remains unsolved but a possible function might be to feed the antigen presentation pathway of the DC.
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Immune cells rely on the activation and collaboration of multiple different receptors in the plasma membrane that are central to leukocyte function. In this context, Annemiek van Spriel (Radboud UMC) discussed the importance of tetraspanin proteins (CD37, CD53) in controlling immunoreceptor organization in the plasma membrane. In B lymphocytes, the tetraspanin CD37 is required for the mobility and clustering of a4b1-integrin (VLA-4) molecules at the cell surface, which is important for plasma cell survival and antibody production in vivo (25). Moreover, tetraspanins can facilitate membrane-proximal signal transduction by their ability to recruit certain signaling molecules (protein kinase C) to the plasma membrane. NK cells are famous for polarized degranulation to destroy their specifically recognized target, a topic investigated by Eric Long (NIH). In NK cells, signals for granule polarization and degranulation are uncoupled, and integrin LFA-1 signaling is sufficient to trigger polarization but not degranulation (26). By use of an elegant proteomics approach with ICAM-1-bearing insect cells as targets and pulldown with anti-p-Tyr (4G10), new LFA-1induced downstream signaling molecules were identified and tested functionally for their role in granule polarization, including ILK (integrin-linked kinase), paxillin, and Pyk2. This ILK signaling network was coupled to a downstream Cdc42-dependent pathway that was also required for granule polarization. Long elaborated mostly on ILK whose involvement was verified by performing proximity ligation assays (duo-link), indicating that ILK-CD18 interaction is induced by ICAM-1. LFA-1 signaling through ILK is sufficient for granule convergence to the microtubuleorganizing center (MTOC) and for polarization of MTOC towards the target cell (27). THERAPEUTIC APPLICATIONS INVOLVING IMMUNORECEPTORS Monoclonal antibody (mAb) therapy is a successful and important treatment for patients with malignancies and autoimmune diseases. All U.S. Food and Drug Administration-approved mAbs are of the IgG class. Jeanette Leusen (University Medical Center Utrecht) explores IgA as a novel type of antibody for treatment of cancer. In most mouse models, she showed that IgA antibodies targeting epidermal growth factor receptor critically depend on the FcR for IgA (FcaRI) for their mode of action. In vitro, polymorphonuclear cells (PMN) are the most important effector cells to kill IgA-opsonized tumor cells, but the exact mechanism is yet unknown. Life imaging of neutrophils killing antibody-opsonized target cells suggest that PMN “eat” parts of tumor cells until they die. Toine ten Broeke from the group of Dr. Leusen showed data that when IgA and IgG antibodies are combined, they can act synergistically through the combination of effector cells. One of the challenges of IgA therapy is the relative short half-life of IgA, especially in mice. Targeting of IgA to the neonatal FcR (FcRn) might overcome this. The FcRn is also the interest of Sally Ward (University of Texas Southwestern Medical Center, Dallas, TX, USA). This receptor is ubiquitously expressed and salvages IgG from lysosomal degradation by pH-dependent binding of IgG in the endocytic system, sorting into tubulovesicular MEETING REPORT ON IMMUNORECEPTORS 2014
transport carriers, and return to the cell surface where it is released into the extracellular space. In the clinic, mAbs directed against soluble factors (e.g. cytokines) are used. Efficacy of such therapies can, however, be hampered by FcRn-mediated redirection of mAb-targeted molecules into the recycling pathway, resulting in an “antibodybuffering” effect that increases the persistence of target molecules. Ward has been engineering mAbs that release their target at endosomal pH, thereby circumventing this problem. Alternative ways to inhibit FcRn function by devising mAbs that bind more strongly to FcRn, and are less pH dependent, are also part of this research. An elegant example of this was presented for a more diagnostic setting (positron emission tomography scan) where relatively fast clearance of circulating background radiolabeled mAb following tumor loading is achieved in mice by using FcRn inhibitors or “Abdegs” (28). Mark Hogarth (Burnet Institute, Melbourne, VIC, Australia) has a long track record regarding FcR biology. Preclinical evaluation of vaccines and therapeutic antibodies are often performed in macaques, and in this context, Hogarth looked at interspecies differences in IgG-FcgR interaction. In more detail, it is found that the binding characteristics of human IgG subclasses to the Macaca nemestrina FcgRs can differ profoundly. Further, FcgR expression can vary as illustrated by the observation that FcgRIII is absent, whereas FcgRII is elevated on M. nemestrina neutrophils in comparison to human (29). Considering these studies, Hogarth advocates cautious interpretation of Ab-induced responses in monkeys, and verification in other animal systems is required. Autoimmune disease can be treated by intravenous administration of intravenous immunoglobulin G (IVIG). According to Falk Nimmerjahn (University of ErlangenNuernberg, Erlangen, Germany), the mechanism behind IVIG treatment partly depends on Fc-mediated effects through interaction with the inhibitory FcgRIIB, and on the extent of Fc sialylation. Mouse models using highly pure mono- or disialylated IgG glycoforms have an enhanced activity, and IVIG may restore immune homeostasis by normalizing serum IgG sialylation. Experiments with human bone marrow reconstituted mice have verified the requirement of sialylation for IVIG activity (30). The apparent role of sialylation also supports the involvement of C-type lectin receptors (DC-SIGN, CD22) that upon blockage can modulate IVIG activity in mouse models. REFERENCES 1. Leusen, J. H. W. (2012) Immunoreceptors: Evolution, structure and therapeutic applications. EMBO Rep. 13, 1046–1048 2. Springer, T. A., and Dustin, M. L. (2012) Integrin inside-out signaling and the immunological synapse. Curr. Opin. Cell Biol. 24, 107–115 3. Flajnik, M. F., Deschacht, N., and Muyldermans, S. (2011) A case of convergence: Why did a simple alternative to canonical antibodies arise in sharks and camels? PLoS Biol. 9, e1001120 4. Herrin, B. R., and Cooper, M. D. (2010) Alternative adaptive immunity in jawless vertebrates. J. Immunol. 185, 1367–1374 5. Sandstrom, A., Peign´e, C. M., L´eger, A., Crooks, J. E., Konczak, F., Gesnel, M. C., Breathnach, R., Bonneville, M., Scotet, E., and Adams, E. J. (2014) The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vg9Vd2 T cells. Immunity 40, 490–500 6. Kjer-Nielsen, L., Patel, O., Corbett, A. J., Le Nours, J., Meehan, B., Liu, L., et al. (2012) vMR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723
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7. Liu, B., Chen, W., Evavold, B., and Zhu, C. (2014) Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell 157, 357–368 8. Garcia, C. K., Adams, J. J., Feng, D., and Ely, L. K. (2009) The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat. Immunol. 10, 143–147 9. Van Laethem, F., Sarafova, S. D., Park, J., Tai, X., Pobezinsky, L., Guinter, T., Adoro, S., Adams, A., Sharrow, S. O., Feigenbaum, L., and Singer, A. (2007) Deletion of CD4 and CD8 coreceptors permits generation of abT cells that recognize antigens independently of the MHC. Immunity 27, 735–750 10. Van Laethem, F., Tikhonova, A., Pobezinsky, L., Tai, X., Kimura, M., Le Saout, C., et al. (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154, 1326–1341 11. Birnbaum, M., Mendoza, J., Sethi, D., Dong, S., Glanville, J., Dobbins, J., et al. (2014) Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157, 1073–1087 12. Yin, L., Scott-Browne, J., Kappler, J. W., Gapin, L., and Marrack, P. (2012) T cells and their eons-old obsession with MHC. Immunol. Rev. 250, 49–60 13. Lu, J., Marjon, K. D., Mold, C., Du Clos, T. W., and Sun, P. D. (2012) Pentraxins and Fc receptors. Immunol. Rev. 250, 230–238 14. Szalai, A. J., McCrory, M. A., Xing, D., Hage, F. G., Miller, A., Oparil, S., Chen, Y. F., Mazzone, M., Early, R., Henry, S. P., Zanardi, T. A., Graham, M. J., and Crooke, R. M. (2014) Inhibiting C-reactive protein for the treatment of cardiovascular disease: Promising evidence from rodent models. Mediators Inflamm. 2014, 353614 15. Hu, X.-Z., Wright, T. T., Jones, N. R., Ramos, T. N., Skibinski, G. A., McCrory, M. A., Barnum, S. R., and Szalai, A. J. (2011) Inhibition of experimental autoimmune encephalomyelitis in human C-reactive protein transgenic mice is FcgammaRIIB dependent. Autoimmune Dis. DOI: 10.4061/2011/484936 16. Lu, J., Yu, Y., Zhu, I., Cheng, Y., and Sun, P. D. (2014) Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis. Proc. Natl. Acad. Sci. USA 111, 5189–5194 17. Cox, N., Pilling, D., and Gomer, R. H. (2014) Distinct Fcg receptors mediate the effect of serum amyloid p on neutrophil adhesion and fibrocyte differentiation. J. Immunol. 193, 1701–1708 18. Wang, M. S., Messersmith, R. E., and Reed, S. M. (2012) Membrane curvature recognition by C-reactive protein using lipoprotein mimics. Soft Matter 8, 7909–7918 19. Su, L., Kidd, B., Han, A., Kotzin, J., and Davis, M. (2013) Virusspecific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–383
20. McMillan, S. J., Sharma, R. S., Richards, H. E., Hegde, V., and Crocker, P. R. (2014) Siglec-E promotes b2-integrin-dependent NADPH oxidase activation to suppress neutrophil recruitment to the lung. J. Biol. Chem. 289, 20370–20376 21. Olde Nordkamp, M. J. M., Koeleman, B. P., and Meyaard, L. (2014) Do inhibitory immune receptors play a role in the etiology of autoimmune disease? Clin. Immunol. 150, 31–42 22. Steevels, T. A. M., Lebbink, R. J., Westerlaken, G. H. A., Coffer, P. J., and Meyaard, L. (2010) Signal inhibitory receptor on leukocytes-1 is a novel functional inhibitory immune receptor expressed on human phagocytes. J. Immunol. 184, 4741–4748 23. Van Avondt, K., Fritsch-Stork, R., Derksen, R. H. W. M., and Meyaard, L. (2013) Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus. PLoS ONE 8, e78459 24. Suzuki, R., Leach, S., Liu, W., Ralston, E., Scheffel, J., Zhang, W., Lowell, C. A., and Rivera, J. (2014) Molecular editing of cellular responses by the high-affinity receptor for IgE. Science 343, 1021–1025 25. van Spriel, A. B., de Keijzer, S., van der Schaaf, A., Gartlan, K. H., Sofi, M., Light, A., Linssen, P. C., Boezeman, J. B., Zuidscherwoude, M., Reinieren-Beeren, I., Cambi, A., Mackay, F., Tarlinton, D. M., Figdor, C. G., and Wright, M. D. (2012) The tetraspanin CD37 orchestrates the a(4)b(1) integrin-Akt signaling axis and supports long-lived plasma cell survival. Sci. Signal. 5, ra82 26. Bryceson, Y. T., March, M. E., Barber, D. F., Ljunggren, H. G., and Long, E. O. (2005) Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J. Exp. Med. 202, 1001–1012 27. Zhang, M., March, M., Lane, W., and Long, E. (2014) A signaling network stimulated by beta2 integrin promotes the polarization of lytic granules in cytotoxic cells. Sci. Signal. 7, ra96 28. Ward, E. S., Velmurugan, R., and Ober, R. J. (2014) Targeting FcRn for therapy: From live cell imaging to in vivo studies in mice. Immunol. Lett. 160, 158–162 29. Trist, H. M., Tan, P. S., Wines, B. D., Ramsland, P. A., Orlowski, E., Stubbs, J., Gardiner, E. E., Pietersz, G. A., Kent, S. J., Stratov, I., Burton, D. R., and Hogarth, P. M. (2014) Polymorphisms and interspecies differences of the activating and inhibitory FcgRII of Macaca nemestrina influence the binding of human IgG subclasses. J. Immunol. 192, 792–803 30. Schwab, I., Mihai, S., Seeling, M., Kasperkiewicz, M., Ludwig, R. J., and Nimmerjahn, F. (2014) Broad requirement for terminal sialic acid residues and FcgRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur. J. Immunol. 44, 1444–1453
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