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Origin and Evolution of Adaptive Immunity Thomas Boehm and Jeremy B. Swann Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; email: [email protected], [email protected]

Annu. Rev. Anim. Biosci. 2014. 2:259–83

Keywords

First published online as a Review in Advance on November 8, 2013

antigen receptor, somatic diversification, lymphocyte, lymphoid organ

The Annual Review of Animal Biosciences is online at animal.annualreviews.org This article’s doi: 10.1146/annurev-animal-022513-114201 Copyright © 2014 by Annual Reviews. All rights reserved

Abstract The evolutionary emergence of vertebrates was accompanied by major morphological and functional innovations, including the development of an adaptive immune system. Vertebrate adaptive immunity is based on the clonal expression of somatically diversifying antigen receptors on lymphocytes. This is a common feature of both the jawless and jawed vertebrates, although these two groups of extant vertebrates employ structurally different types of antigen receptors and principal mechanisms for their somatic diversification. These observations suggest that the common vertebrate ancestor must have already possessed a complex immune system, including B- and T-like lymphocyte lineages and primary lymphoid organs, such as the thymus, but possibly lacked the facilities for somatic diversification of antigen receptors. Interestingly, memory formation, previously considered to be a defining feature of adaptive immunity, also occurs in the context of innate immune responses and can even be observed in unicellular organisms, attesting to the convergent evolutionary history of distinct aspects of adaptive immunity.

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INTRODUCTION

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Jawless vertebrates: the most basal group of vertebrates, comprising approximately 100 species of lampreys and hagfish Jawed vertebrates: a group consisting of cartilaginous fishes, bony fishes, amphibians, reptiles, birds, and mammals HSC: hematopoietic stem cell

The discovery of an alternative adaptive immune system in jawless vertebrates (1, 2) affords the unexpected opportunity to examine general principles of vertebrate immune systems (3–14). Whereas the immune systems of jawless vertebrates, such as hagfish and lamprey, and jawed vertebrates, comprising species as diverse as sharks and humans, clearly differ in many molecular and mechanistic aspects, recent studies have nonetheless revealed a surprising degree of morphological, cytological, molecular, and functional similarity (15–21). Hence, in-depth, comparative studies of vertebrate immune systems not only yield important insights into the minimal set of components required for an adaptive immune system but also provide the basis for the reconstruction of the immune system of the extinct common vertebrate ancestor. In this review, we highlight recent findings on the immune systems of jawless fishes and contrast them with the results of studies in lower-jawed vertebrates. We begin by discussing key aspects of the morphological basis of vertebrate immune systems, namely, lymphocytes and lymphoid tissues, and then discuss the different types of antigen receptors that are somatically assembled from incomplete gene segments during lymphocyte development. We continue with a description of ecological pressures favoring the emergence of complex antigen receptor repertoires. A summary of the many variations of immune faculties in different vertebrate species is followed by a discussion of the essential features of adaptive immunity, with reference to its evolutionary roots in nonvertebrate species.

LYMPHOID ORGANS Lymphoid organs are present in all vertebrates (22); based on functional criteria, they are commonly divided into two categories: primary and secondary lymphoid tissues. Primary lymphoid organs, such as bone marrow and the thymus, provide specialized stromal microenvironments that foster the generation of the primary repertoire of B and T lymphocytes. By contrast, secondary lymphoid tissues specialize in the coordination of immune responses by spatially organizing the interaction of immune effector cells, such as antigen-presenting cells and lymphocytes. Hence, all lymphoid tissues/areas exhibit characteristic appositions of specific hematopoietic cell types and distinct stromal components, which underlie the functional specializations of primary and secondary lymphoid tissues. The approximate time of their evolutionary emergence is illustrated in Figure 1. Lymphocytes, like all other hematopoietic cells, are descendants of hematopoietic stem cells (HSCs); HSCs are situated in general hematopoietic tissues that are often, but not always, associated with the gut tube. Lamprey larvae, for example, exhibit hematopoietic activity in the typhlosole, an invagination of the gut wall (23). Cartilaginous fishes possess the so-called Leydig’s organ, which is attached to the esophagus; the spiral valve, a specialized region of the lower intestine; and the epigonal organ, which is attached to the ovaries (24). Interestingly, gutassociated lymphoid aggregates (referred to as GALTs) exist in all extant vertebrates (25) and hence were presumably also present in the common vertebrate ancestor. General hematopoietic tissues (termed bone marrow equivalents in Figure 1), which in vertebrates support the development of the various myeloid and early lymphoid cell lineages, predate the emergence of vertebrates (26). Hematopoiesis takes place in gut-associated hematopoietic tissue and also in the kidney in fishes and the bone marrow in tetrapods. A universal feature of vertebrates is that B cells develop in these general hematopoietic organs within specialized niches; these stromal microenvironments are distinguished by the expression of specific factors, such as the chemokine CXC ligand (CXCL)12 and the cytokine interleukin (IL)7 (27, 28), both of which are also important for

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Figure 1 Evolutionary emergence of lymphoid tissues. The mammalian immune system is characterized by the presence of several distinct hematopoietic and lymphoid tissues (listed at the top), of various evolutionary origins. The time points when major groups of vertebrates emerged are indicated on the left (159); vertical bars indicate the time of emergence of different tissue types. Abbreviations: GALT, gut-associated lymphoid aggregate tissue; Ma, million years.

the development of T cells in the thymus (29). Such general-purpose factors must synergize with other niche-specific stromal molecules, such as FLT3, to specifically support the development of B cells (30). The thymus is an ancient primary lymphoid organ and is always located in the pharynx, presumably because its epithelial stromal component derives from the pharyngeal endoderm (11); this morphological characteristic contrasts with the remarkable anatomical diversification of sites for B cell development, as discussed above. Thymopoietic tissues [referred to as thymoid in lamprey larvae (31) and thymus in jawed vertebrates] specialize in supporting T cell development and selection for self-compatibility and thus appear to be ancient components of the vertebrate body plan and immune system. Thymopoietic epithelia universally express the gene encoding the transcription factor FOXN1 (32, 33). This factor is likely involved in regulating expression of chemokines (CXCL12 in lamprey; CCL25 and CXCL12 in fish embryos; CCL25, CXCL12, and CCL21 in mouse embryos) attracting hematopoietic progenitor cells to the thymic rudiment and in the control of a critical lineage-specification molecule, the NOTCH1 ligand DLL4 (34–36). Further research could conceivably lead to the discovery of more molecules contributing to the function of

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thymopoietic tissues of different kinds of vertebrates. In this context, we stress the remarkable morphological similarities between the thymoids of cartilaginous fishes and mammals; however, because of the small size of individual thymoids, it is unclear whether the thymopoietic tissues of jawless fishes adhere to the same principle and likewise consist of cortical and medullary regions (Figure 2a–d). Although the general positioning of thymopoietic tissues in the pharyngeal region is a conserved feature of all vertebrates, the precise anatomical location and organization of thymopoietic tissues vary considerably among different species. In lamprey larvae, thymopoietic tissues (termed thymoids) are found at the tips of gill filaments throughout the entire gill basket (31); in sharks, thymic tissue is associated with some but not all pharyngeal arches (37); in teleosts, most thymic tissue emanates from the third pharyngeal pouch (38); in birds, several thymic lobes are arranged in a string-like pattern throughout the neck (39); and in mammals, most thymopoietic tissue is found in the thoracic thymus (40), although additional thymic tissue is often localized in the neck region (41, 42). We have suggested that a placode-like structure consisting of thymus-specific epithelial progenitor cells develops in early vertebrate embryos (33), wherein each of these epithelial progenitors is capable of organizing a functionally autonomous thymopoietic unit (43, 44). Depending on the extent of tissue rearrangements occurring in the developing pharynx, these thymopoietic units might become dispersed (as in lamprey larvae) or maintained as one or several tissue aggregates (as in jawed vertebrates), possibly involving more than one specification event

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Figure 2 Morphological similarities of thymopoietic tissues. (a) A section across a gill filament of lamprey larvae (Lampetra planeri) illustrates the presence of the lymphoepithelial thymoid structure, which is highlighted by a dotted line; hematoxylin-eosin staining. (b) Histological appearance of the thymus of cartilaginous fishes (Scyliorhinus canicula), with the cortical (c) and medullary (m) regions indicated; hematoxylin-eosin staining. (c) Histological appearance of the thymus of mouse (Mus musculus); hematoxylin-eosin staining. (d) Developmental relationship of cortical and medullary thymic epithelial types that originate from a common progenitor cell via intermediate precursors; the descendants of a single thymic epithelial stem cell (TESC) are defined as a thymic epithelial developmental unit (TEDU). (e) Developmental fate of a certain number n of TEDUs; during embryonic development, they either disperse (as possibly occurs in lamprey) or coalesce (as occurs in jawed vertebrates).

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during embryogenesis (33) (Figure 2e). The partially overlapping set of molecular components of the B cell– and T cell–specific niches in primary lymphoid organs is illustrated in Figure 3; note that shared factors are expressed in mesenchymal and epithelial cells, respectively (i.e., they are derived from different germ layers), illustrating the selective forces underlying the convergent evolution of lymphoid tissues. It is also notable that the presence of many different hematopoietically important factors affords the possibility of generating a plethora of functionally distinct niches, each distinguished by coexpression of a different subset of such factors. This subfunctionalization of niches might facilitate the consecutive differentiation of hematopoietic cell lineages, including B cells in the general hematopoietic tissues. In the thymus, such subfunctionalization might underlie the functional distinction of the different cortical and medullary compartments (45–47); for example, DLL4, the critical ligand for NOTCH1 on hematopoietic cells, is a dedicated thymopoietic factor, as it directs the specification of immature progenitors to the T cell lineage (48, 49). The spleen is the evolutionarily most ancient example of a secondary lymphoid organ (50). During development in jawed vertebrates, it is sequentially colonized by different types of lymphoid cells, eventually giving rise to the species-specific microanatomy of the white pulp that coordinates the interaction of different immune effector cells; small foci of lymphoid cells in intestinal hematopoietic areas of lamprey are considered to be the equivalent of the spleen (51). When considering the precise microanatomical characteristics of the spleen in cartilaginous fishes, bony fishes, amphibia, reptiles, birds, and mammals, it becomes obvious that there is a continual increase in morphological complexity; this histological diversification parallels the increase in complexity of immune-related effector cells regulating the immune response (22).

Lymphoid progenitor

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SCF IL7 CXCL12 DLL4 FLT3

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b Supports TCRαβ+CD4+CD8+ development

Figure 3 Shared molecular components of lymphoid tissue environments. (a) Schematic indicating the similarities of stromal components that support B and T cell development. The B cell niche is characterized by the presence of FLT3, interleukin 7 (IL7), and CXC ligand (CXCL)12, whereas the T cell niche in thymopoietic tissues additionally expresses the critical Notch ligand DLL4. Note that the B cell niche is of mesenchymal origin, whereas the T cell niche universally consists of thymic epithelial cells. (b) Differential expression of niche components creates functional diversity; one particular type of niche in the thymopoietic environment (DLL4 and CXCL12) supports the development of immature precursors to the CD4þCD8þ double-positive stage of thymocyte development.

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LTi: lymphoid tissue inducer LTo: lymphoid tissue organizer

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Lower vertebrates: a group consisting of jawless and jawed fishes

Building upon the basic lymphatic system of teleosts, lymph nodes represent the only major recent morphological innovation of the vertebrate adaptive immune system, dating back to the emergence of reptiles and birds (52, 53). The tissue environments of lymph nodes promote the cellular interactions that lead to T cell activation and the affinity maturation of antibodies and, consequently, efficient memory responses (54, 55). Lymph nodes are believed to have evolved through regional specialization of lymph vessels in such a way that interactions with the local tissue environment facilitated the occurrence of lymphoid aggregations at these sites (56, 57). The distinct phenotypes of mice mutant for one or more genes of the tumor necrosis factor (TNF) family of ligands and receptors suggest that the emergence of lymph nodes is closely connected to the evolutionary emergence of these gene families (58). The same arguments apply to the expansions of the chemokine and chemokine receptor gene families and the emergence of special types of innate lymphocytes [such as lymphoid tissue inducer (LTi) cells] that are also associated with the acquisition of lymph nodes in land-living vertebrates. Interestingly, LTi cells, although required for the development of these innovative secondary lymphoid structures, are dispensable for their primordial types, such as the spleen (59), reinforcing the notion of the presence of functionally convergent but molecularly distinct secondary lymphoid tissues. This theme of shared function but different origins is echoed by the stromal cells underlying the formation of different secondary lymphoid organs in the form of lymphoid tissue organizer (LTo) cells. For example, the stromal compartment of the spleen originates from the dorsal pancreatic mesenchyme; surprisingly, it does not contribute to gut-associated secondary lymphoid tissues, such as Peyer’s patches (60). By contrast, the LTo cells of peripheral lymph nodes are descendants of adipocytes, which become reprogrammed into LTo by signaling through the lymphotoxin b receptor (LTbR), an evolutionarily recent member of the TNF receptor gene family (61). This functional requirement adds an additional facet to the molecular framework, explaining the evolutionary emergence of peripheral secondary lymphoid tissues (Figure 4). In conclusion, the evolutionary trajectory of lymphoid tissues of vertebrates is characterized by (a) the early emergence of primary lymphoid organs and (b) the dynamic elaboration and increasing complexity of secondary lymphoid tissues. In some cases, morphological novelties can be linked to the emergence of new genes, a phenomenon that is particularly relevant to the development of lymph nodes.

LYMPHOCYTES The main cellular effectors of adaptive immune reactions are the lymphocytes. Lymphocytes represent an evolutionarily recent hematopoietic cell type that is universally present in vertebrates; by contrast, evidence for similar cells in chordates is not well documented (11). Although cells resembling vertebrate lymphocytes have been observed in amphioxus, no evidence exists to suggest that they proliferate in response to antigen exposure, a defining feature of vertebrate lymphocytes (62). The immune systems of all vertebrates are distinguished by the presence of two major lymphocyte lineages (2,63). This dichotomy is reflected in the distinct genetic networks regulating the development of T and B cells (64–66), the separate anatomical locations where development takes place, and the functional differences between their antigen receptors (1, 2, 67–69) (Figure 5). In jawed vertebrates, B cells develop in the bone marrow or its functional equivalents. Several of the key transcription factors required for B cell development in mice, such as PAX5 and E2A (70), also appear to be expressed during the development of B cells in lower vertebrates, suggesting that the genetic networks underlying B cell development are evolutionarily conserved (71–74). Indeed, homologs of (at least some of) these genes are also present in the lamprey genome and are 264

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LTo

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Secondary lymphoid tissue

Figure 4 The role of lymphoid tissue organizer (LTo) and lymphoid tissue inducer (LTi) cells in the development of secondary lymphoid organs. Secondary lymphoid organs, such as the spleen and lymph nodes, depend on the presence of so-called LTo cells that appear to have different embryological origins. The LTo cells giving rise to the spleen arise from dorsal pancreatic mesenchyme, whereas those giving rise to peripheral lymph nodes descend from preadipocytes, which, upon retinoic acid signaling, differentiate into LTo cells; this process depends on lymphotoxin b receptor (LTbR) signaling. LTo cells typically express the LTbR and the CXCL13 chemokine; this attracts so-called LTi cells that provide a ligand, lymphotoxin (LTa1b2), to support the further differentiation of LTo cells into the different stromal components of secondary lymphoid organs. Note that the differentiation of the lymphoid structure of the spleen is independent of the presence of LTi cells, which explains why this organ is already present in lower vertebrates (see Figure 1) that lack both LTi cells and the LTbR/LT axis.

preferentially expressed in their B-like lineage (2), indicating that the genetic program underlying the development of antibody-producing lymphocytes antedates the emergence of the two sister groups of vertebrates. In mice, B cell development depends on the simultaneous activities of IL7 and FLT3 ligand, which are therefore considered to be crucial components of the B cell niche (30), the cellular origin of which is the mesenchymal germ layer (Figure 3). However, it is at present unclear whether homologs of IL7 and FLT3 ligand exist in basal vertebrates or whether other factors regulate B cell development in these species. The Notch signaling pathway, employing the NOTCH1 receptor and its ligand DLL4, is required for the specification of the T cell lineage (48, 49). Lymphoid precursor cells are attracted to the thymus—the main site of T cell differentiation in all vertebrates—by chemokine gradients emanating from the thymic microenvironment (35, 36, 75), and they are then exposed to the specific Notch ligand that initiates the T cell–differentiation program. From reconstitution experiments in vivo, it has become apparent that CXCL12, a chemokine and growth factor for early thymocytes, is a key contributor to the initial stages of T cell differentiation (76); in fact, the presence of only CXCL12 and DLL4 in the thymic microenvironment (Figure 3) is sufficient to support T cell development until the CD4þ/CD8þ double-positive stage (77). However, in its present form, this experimental paradigm, which relies on transgenic re-expression of individual effector molecules in functionally incapacitated, Foxn1-deficient thymic epithelia, is unsuitable for examining the molecular requirements of subsequent differentiation. Rather, further refinement of

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Adaptive Immunity

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TCR: T cell receptor

this system is necessary to ensure the expression of self-peptide/major histocompatibility (pMHC) complexes, which are required for the positive selection of the immature T cells. Although this is essential for the differentiation of T cells expressing the ab T cell receptor (TCR) (78), interactions with pMHC complexes are not necessary for the development of T cells expressing the gd TCR (79). When only CXCL12 and DLL4 are present in the thymic microenvironment, lymphoid progenitors fail to enter the alternative developmental pathway, and as a result, no gd T cells can be detected in the reconstituted thymic lobes (77); when considering candidates for gd T cell–lineage reconstitution, IL7 deserves special attention. IL7 is necessary for the gd T cell lineage (80, 81) but also supports B (82) and ab T cell development (29). However, neither IL7 nor IL7R genes have so Extant gnathostomes

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Figure 5 Lymphocyte lineages of vertebrates. (a) Both jawless and jawed vertebrates possess several lymphoid lineages (see Reference 11 for a detailed discussion). In jawed vertebrates, evidence for two principal B cell and two principal T cell lymphocyte lineages has been obtained. Genetically distinct B cell lineages have been described only for teleosts, expressing either immunoglobulin (Ig)M or IgZ; although distinct B1 and B2 types of B cells have been recognized in mammals, they both express IgM as their principal Ig. In all vertebrates, the two T cell lineages express either the ab T cell receptor (TCR) or the gd TCR. Note, however, that these principal lineages further differentiate into various sublineages. In B cells, subfunctionalization is often accompanied by the so-called isotype switch, where B cells exchange the constant regions of Igs to produce, for instance, IgG or IgE. In the gd T cell lineages, functionally distinct subsets are characterized by particular TCR repertoires that differ between cells localized in different tissues, such as skin or mucosal surfaces. In the ab T cell lineage, differentiation is accompanied by restriction to antigens presented by either MHC class I or II molecules and expression of particular effector chemokines and cytokines. In jawless vertebrates, one B cell lineage expressing variable lymphocyte receptor (VLR)B has been described; the two related VLRA and VLRC types of VLRs are expressed by different lineages, which, however, appear to be developmentally related as judged by the nature of their gene assemblies (160). (b) Because both groups of vertebrates exhibit multiple lymphocyte lineages, the common vertebrate ancestor may have already possessed a similarly complex lymphocyte lineage structure. However, it should be noted that the somatic diversification process that underlies the formation of antigen receptors in extant vertebrates emerged separately in the jawless and jawed vertebrates and therefore was presumably not present in their common ancestor. This conclusion rests on the observation that the types of genes subjected to somatic diversification differ (VLRs versus Ig/TCR), as do the relevant mechanisms [gene conversion versus variable-diversity-joining (VDJ) recombination]. The hypothetical intermediates of primordial B-like (ur-B cell) and T-like (ur-T cell) lymphocytes and their common ancestor (ur-lymphocyte) remain elusive and may have been present in now-extinct representatives of chordates and/or primordial vertebrates.

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far been identified in cartilaginous fishes; whether this indicates that IL7/IL7R signaling function might be less evolutionarily conserved than that of the CXCL12/CXCR4 and DLL4/NOTCH1 signaling pathways awaits detailed genomic and transcriptional analyses of these evolutionarily important representatives of jawed vertebrates. Nonetheless, such reconstitution experiments have the potential to delineate the minimal set of extrinsic factors required for the development of mature T cell subsets in the thymus and also to provide an experimental strategy for examining the essential requirements for the B cell lineage.

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STRUCTURES OF ANTIGEN RECEPTORS OF VERTEBRATES The antigen receptors of jawed vertebrates belong to the immunoglobulin (Ig) superfamily (8). The defining feature of this family of proteins is the so-called Ig fold of antiparallel b-sheets; this unique protein domain is approximately 100 amino acid residues in length and is characterized by an intrachain disulphide bond. B cell receptors (BCRs) and TCRs possess several Ig folds, and both are obligate hetero-oligomers; they are composed of two membrane-spanning heavy chains and two associated light chains, in the case of Igs (although single-chain antibodies are present in various species), and two membrane-spanning molecules (either a and b or g and d), in the case of TCRs. Variant forms of these antigen receptors are additionally present in cartilaginous fishes. Functional antigen receptor genes are not germline encoded but are instead formed in developing lymphocytes by a process termed V(D)J recombination (83): Catalyzed by the recombination-activating gene (RAG) family proteins, variable (V)-, diversity (D)-, and joining (J)-type segments are joined together into complete genes (Figure 6a). In addition to the combinatorial use of these sequence elements, nontemplated nucleotides are introduced at the junctions during the assembly process. These non–germline encoded regions typically encode part of the antigen-binding surfaces of the antigen receptors (commonly referred to as complementarity determining region 3) (Figure 6b) and thus significantly contribute to the structural diversity of functional BCRs and TCRs. By contrast, the antigen receptors of jawless fishes consist of leucine-rich-repeat (LRR)containing proteins (4, 12), structural motifs that are also present in receptors relevant for innate immunity, such as Toll-like receptors. The LRR motif is 24 amino acids long and folds into a b-strand-turn-a-helix configuration. Three types of variable lymphocyte receptors (VLRs), termed VLRA, VLRB, and VLRC, are known in lampreys; these are expressed as membranebound proteins and possess a similar overall domain structure. As with Ig and TCR genes, VLR genes are present in the genome in incomplete form. Assembly of mature VLR receptors by insertion of LRR modules (Figure 6c) is thought to depend on the activities of cytosine deaminases (CDAs) of the AID-APOBEC family (84): CDA1 (for VLRA, but possibly also VLRC assembly) and CDA2 (for VLRB assembly) (2), in a process akin to gene conversion (85). The variable internal LRR segments encode the antigen-binding surfaces (Figure 6d) (86–91). During lymphocyte development, the noncoding intervening sequence of a germline VLR gene (Figure 6e) is replaced in a stepwise manner, presumably based on short stretches of sequence homology at the ends of the individual segments (4, 85, 92). Assembly can begin at either end (Figure 6f), eventually forming a completely assembled VLR gene (Figure 6g) (93). Sequence diversity is detected primarily in the central portions of the molecules and is generated by combinatorial use of the individual LRR segments of the VLRs, but also by variable positioning of the crossover points during the assembly of germline-encoded elements; accordingly, the germline-encoded invariant N- and C-terminal components of VLRs contribute little to interaction with antigens. VLRA and VLRC are likely transmembrane proteins and are not secreted (2); VLRB, while being anchored to the cell membrane by glycophosphatidylinositol linkage (2), is also secreted as an antibody-like molecule by mature plasmacytes (88, 94). Like IgM (95), the secreted form of VLRB is thought to form www.annualreviews.org



Adaptive Immunity

Ig: immunoglobulin BCR: B cell receptor V(D)J recombination: a gene-rearrangement process involving RAG-mediated recombination in the variable BCR- and TCR-encoding genes in jawed vertebrates RAG: recombinationactivating gene VLR: variable lymphocyte receptor CDA: cytosine deaminase Gene conversion: a form of homologous recombination that is initiated by DNA double-strand breaks and results in nonreciprocal transfer of genetic information

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Somatic diversification: a process resulting in changes to the germline sequence of genes in individual cells that are retained by cell progeny

multimers (94), attesting to the remarkable functional similarity between the antibody-like molecules of jawless and jawed vertebrates. Many examples of apparent somatic diversification of presumptive antigen receptors have also been described in invertebrates, likely representing the preadaptive states of their immune systems. For instance, alternative splicing of the arthropod DSCAM genes gives rise to thousands of isoforms, extensive RNA editing of transcripts of Sp185/333 genes in sea urchin affords somatic diversification, hypermutation of genes encoding fibrinogen-related proteins (FREPs) in mollusks appears to function in immune-related non-self-recognition, and extensive polymorphism of variable chitin-binding proteins (VCBPs) has been linked to immune homeostasis in chordates (96). The plethora of mechanisms invoked in immune defense attests to the selective pressure on multicellular organisms exerted by their parasites.

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EVOLUTIONARY ORIGIN OF ANTIGEN RECEPTOR GENES Primordial versions of the genes eventually subjected to somatic diversification in vertebrate lymphocytes are thought to have been present in the genome of the vertebrate common ancestor (3–5, 7–9, 11, 12). VLR proteins are related to the vertebrate-specific glycoprotein Ib a membrane protein (84); likewise, chordate genomes contain genes encoding ancestral Ig-like and TCR-like proteins (97; 98). Whereas the CDA genes implicated in VLR diversification in jawless fishes are derived from ancient components of a defense mechanism that targeted foreign genetic material (99), the genes encoding the RAG recombinases are thought to have been incorporated into the genomes of gnathostomes via lateral gene transfer by transposases [possibly related to the ancient family of Transib transposases (100)] after the divergence from cyclostomes (101). Interestingly, RAG-like genes have also been detected in invertebrates such as sea urchins (102), indicating that their specific role in adaptive immunity was subsequently acquired. This apparent evolutionary discontinuity with respect to antigen receptor structures and diversification mechanisms supports the notion of the independent evolutionary origins of diversification mechanisms in the two sister groups of vertebrates. Because both groups of vertebrates possess at least one B and two major T cell lineages (2, 103), it appears likely that the same types of lymphocyte lineages already existed in the common ancestor of all vertebrates but were probably not subjected to somatic diversification. It remains unclear whether the primordial versions of the VLR and Ig/TCR genes already served as antigen receptors for the lymphocytes of early vertebrates or whether other proteins were employed for this purpose. Given that somatically diversifying and germline-encoded receptors are coexpressed in modern lymphocytes, and that these molecules serve distinct functions, the ancestors of somatically diversifying antigen receptors likely already participated in immune functions, albeit in germlineencoded forms.

REPERTOIRE DEVELOPMENT The processes of somatic diversification of antigen receptor genes observed in jawless and jawed vertebrates are extremely efficient; in fact, considering the number of lymphocytes that are found in representative species and a minimum number of cells per clone, somatic diversification of antigen receptors tends to exceed the possibilities of their clonal representation. For instance, an extrapolation from mammals (104) indicates that the largest mammal, the blue whale, Balaenoptera musculus, has approximately 1016 lymphocytes; assuming a minimum clone size of 100 cells, the potential sequence diversity of gd TCRs of approximately 1015 (68) alone exceeds the possibilities of clonal representation. The same is probably true for the largest fish, the whale shark, Rhincodon 268

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CDR3 VLRC genomic locus

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Figure 6 Assembly of immunoglobulin (Ig)/ T cell receptor (TCR) and variable lymphocyte receptor (VLR) genes. (a) Assembly of Ig/TCR genes by variable-diversity-joining [V(D)J] recombination. A single V element (Vi) out of many is chosen together with a single J element (Ji), again out of many, for fusion by nonhomologous end joining. This process is error prone and is mediated by Rag recombinase proteins, which recognize so-called signal sequences situated at the ends of gene segments; the introduction of nontemplated nucleotide residues at the junctions considerably increases the diversity of the resulting assembled antigen receptor genes beyond the diversity introduced by a combinatorial choice of elements. Note that in some cases, for instance, in the Ig heavy chain and the TCRb chain genes, an extra diversity element, D, is additionally incorporated between V and J elements, creating an additional opportunity for nontemplated sequence diversity. The V/J or V/D/J junction encodes the so-called CDR3 region that forms an important part of the antigen contact surface of antigen receptors. (b) Structure of a mature Ig/TCR protein. The variable element Vi is fused to a joining element, Ji, that is appended to a constant region C domain. Note the position of the so-called CDR3 domain, the nucleotide sequence of which is generated by the VDJ recombination process and consists of nontemplated nucleotide residues introduced by nonhomologous end joining; the CDR3 domain forms an important part of the antigen-binding surface of Ig/TCR antigen receptors. (c) Schematic of the assembly process of VLR genes. The known VLRA, VLRB, and VLRC genes all consist of incomplete genomic loci that are flanked by additional elements required to complete the formation of a mature VLR gene, here illustrated by leucine-rich-repeat (LRR) modules. (d) Structure of a mature VLR protein. Similar to their Ig/TCR counterparts, these antigen receptors possess antigen-binding surfaces that are generated by multimers of internal LRR domains that are introduced into the germline sequences of VLR genes by gene conversion from a large genomic repertoire of variable LRR modules. (e–g) An example of VLR gene assembly (for details, see Reference 93). (e) Schematic of the germline VLRC locus of Lampetra planeri. The locus is incomplete, as it encodes only N- and C-terminal portions of the mature VLR. (f) The necessary additional elements are appended in a stepwise fashion, beginning either from the 50 end or from the 30 end. (g) Eventually, the mature VLRC gene is formed and consists of variable numbers of internal LRR modules (LRRi) that are thought to encode the binding surface for antigens. Abbreviations: CDR, complementarity-determining region; CP, connecting peptide; LRRNT, N-terminal leucine-rich region; LRRCT, C-terminal leucine-rich region; SP, signal peptide.

typus. More direct information is available for the antigen receptor repertoires of vertebrates with smaller body size. For instance, the antibody repertoire of zebrafish comprises approximately 5 3 103 different Ig heavy-chain sequences per fish (105); given a total number of approximately 1–5 3 106 lymphocytes per fish, this result suggests an upper limit of approximately 1,000 cells per unique

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Ig heavy-chain sequence. If the light-chain repertoire is of a similar magnitude, the potential combinatorial IGH/IGL diversity is likely to not be represented in each animal. A similar situation appears to exist for the repertoire of ab TCRs of mice, which was estimated to be in the order of 2 3 106, equivalent to a clone size of approximately 100 cells (106). Sequencing of the paired human Ig heavy- and light-chain repertoire suggested clone sizes of between approximately 3 and 40 and a sequence complexity of greater than 109 unique BCRs in blood (107). However, because the diversity at the level of primary sequences does not necessarily correspond to diversity at the level of antigen specificity, the number of functionally distinct antigen-binding specificities of vertebrate antigen receptor repertoires is probably much lower, suggesting that a certain degree of antigen receptor promiscuity is required to establish a functionally competent anticipatory repertoire. Although far less is known about the antigen receptor repertoires of jawless fishes, the same principles likely apply. For instance, the sequence diversity of VLRs in jawless fishes is estimated to be in the order of 1014 (12), indicating that even in the most basal vertebrates, sequence diversification exceeds the possibilities of clonal representation in lymphocytes. It is important to note that, as a consequence of the limited possibilities of clonal representation at any given point during the lifetime of an animal, the naïve repertoire is constantly being replenished with specificities that are unrelated to previous ones. The surprisingly efficient somatic diversification mechanisms and the highly diverse sequence repertoires that can be generated involve the risk of producing self-reactive receptor specificities. Hence, mechanisms are required to tame potential autoimmune reactions. These mechanisms are best understood for developing T cells in mammals. Because ab TCRs recognize processed antigens that are displayed on the surface of antigen-presenting cells, efficient assessment of potential self-reactivity requires dedicated tissue environments for the necessary cell-cell interactions. Hence, the thymus might have evolved a dual role during T cell development: It fosters the specification of lymphoid progenitors (22) and then subsequently orchestrates the many selection steps that are required to achieve a self-tolerant repertoire of TCRs (108, 109). Although likely, at present it is unclear whether the diversified VLRA and/or VLRC antigen receptors of lamprey undergo a similar quality-control process. However, it should be noted that alloreactivity has been observed in jawless fishes (51), arguing in favor of the presence of a mechanistically similar, but possibly molecularly distinct antigen-presentation system in these basal vertebrates. Because intrathymic quality control depends on the stochastic nature of cellular interactions of lymphocytes and stromal cells during negative selection, dedicated regulatory cell types might have evolved to deal with unavoidable residual self-reactivity in the repertoire.

MONOALLELIC EXPRESSION OF ANTIGEN RECEPTOR GENES In both jawless and jawed vertebrates, formation of functional antigen receptor genes is achieved by a combinatorial assembly mechanism from incomplete, germline-encoded segments. This assembly process is strictly regulated and ensures that each lymphocyte expresses a single receptor. From a functional point of view, expression of a single receptor per cell has several advantages. It maximizes the efficiency with which a self-tolerant receptor repertoire can be elaborated during lymphocyte development; for example, when the probability of self-reactivity after assembly of a receptor is 50% [a figure not uncommon for BCRs (110) and TCRs (111)], expression of a single receptor maximizes the diversity of the self-tolerant repertoire (11). This can be augmented even further by monoallelic expression. Indeed, the benefits arising from the vast diversity of antigen receptors generated by somatic diversification are counterbalanced by the possibility of their inadvertent reactivity toward self-structures. Although potentially self-reactive forms of germline-encoded 270

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antigen receptors (such as TLRs) are eliminated through natural selection, somatic diversification necessitates innovative solutions to suppress undesired self-reactivity. For instance, in the thymus, complex cellular and molecular mechanisms underlying presentation of self-antigens serve the purpose of dealing with overly self-reactive lymphocytes (see above). Hence, vertebrates achieve a trade-off between increased immune facilities and the risk of autoimmunity. Clonal expression of antigen receptors is also advantageous for antigen-specific memory formation, because exposure to one particular antigen activates only a subset of lymphocytes, namely those that bear the cognate receptor. Because activation of vertebrate lymphocytes entails vigorous proliferation, focusing an immune response is an efficient way to manage the limited resources of trophic factors that are required for lymphocyte survival (112); thus, this strategy helps maintain the diverse repertoire of naïve lymphocytes ultimately required to combat any subsequent infection(s). Despite different assembly mechanisms and molecular structures, antigen receptors of jawless and jawed vertebrates share the common feature of monoallelic expression. This remarkable case of convergent evolution attests to the aforementioned multilayered, functional significance of the monospecificity of antigen receptors expressed by lymphocytes. This observation in turn predicts that VLR-type antigen receptors are also potentially autoreactive, and hence monoallelic expression maximizes the diversity of the self-tolerant repertoire during development (11); moreover, because memory responses are particularly efficient when cells express monospecific antigen receptors, monoallelic expression of VLRs suggests that memory is a feature of the immune systems of jawless vertebrates.

ECOLOGICAL PRESSURES FAVORING THE EMERGENCE OF SOMATIC DIVERSIFICATION IN VERTEBRATES Whereas jawless and jawed vertebrates share many principles of immune system design and development, the molecular details underpinning their immune faculties differ in important ways, as discussed above. This suggests that at some point after divergence, their respective ancestors must have experienced a similar type of selection pressure that eventually led to the evolution of somatic diversification of antigen receptors. A change in habitat may have provided the evolutionary force for the emergence of more sophisticated immune defenses in early vertebrates. However, vertebrate-specific innovations in the immune system may have provided the basis for the evolution of complex, mutualistic relationships between the vertebrate host and beneficial microbes as a way of generating a kind of superorganism with unprecedented metabolic facilities (113). In this view, the ability to generate a diversified antigen receptor repertoire underlies the elaboration of a species-rich, autochthonous microbiome living on and in vertebrates, while at the same time providing the basis to control the constituents of the allochthonous, potentially pathogenic flora (114, 115) (Figure 7). This complex managerial task would have been impossible to achieve for immune systems relying on germline-encoded receptors; the many different receptors required for these functions would have rapidly exceeded the coding capacity of the vertebrate genome. Hence, somatic diversification provided a cost-efficient solution to benefit from the selective advantages of maintaining a species-rich microbiome. Indeed, defective structural diversification of secreted antibodies, such as IgA, is associated with dysbiosis, which is characterized by generally lower species diversity and an unhealthy microbiome composition (116–125). The principle of immunemediated microbial management may antedate the emergence of vertebrates. For instance, it has been hypothesized that variable-region-containing chitin-binding proteins expressed in the intestinal tracts of living chordates, such as amphioxus and tunicates, are involved in shaping resident microbial communities (126, 127). The complex mutualistic interactions evolving in www.annualreviews.org



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Immune responses Metabolic interactions

Diversity of antigen receptors

Figure 7 The relationship between a diversified antigen receptor repertoire and the species richness of the autochthonous microbiome. In the presence of limited diversification of antigen receptors, the number of species inhabiting the organism is small, resulting in weak mutualistic interactions between host and microbiota; at the same time, the host is vulnerable to the detrimental effects of pathogens owing to limited defense capacities. A highly diversified microbiome favors the establishment of complex mutualistic interactions and simultaneously provides enhanced protection against attack by pathogens.

a superorganism may have been accompanied by the emergence of additional regulatory circuits that might have been further elaborated in mammals (128).

ALTERNATIVE SOLUTIONS IN THE ADAPTIVE IMMUNE SYSTEMS OF LOWER VERTEBRATES Immunological research has always benefited from comparative phylogenetic approaches; for instance, the principles of lymphocyte and lymphoid organ development and mechanisms of antigen receptor diversification emerged from work on amphibians (129) and birds (63, 130–132). As a recent example, IgD, an Ig found in mucosal secretions as well as in the blood, was found to play an evolutionarily conserved role in systemic immunity by binding to the cell-surface receptors of basophils (133). In this way, these innate cells are supplied with information about the antigenic composition of, for example, the respiratory tract, which enables them to trigger rapid innate responses. However, apart from gaining a better understanding of the general principles of immune system design and function, it is instructive to consider in detail the species-specific solutions to immunological challenges. The foregoing discussion has provided ample evidence for alternative group-specific solutions achieved by jawless and jawed vertebrates. However, instructive examples for variations on a theme can also be found among the thousands of jawed vertebrate species. A particular focus lies on species-specific innovations in fishes, which comprise a unique group of vertebrates distinguished by their extraordinarily diverse life spans and ecology. For instance, it was discovered recently that a long-lived marine fish, the Atlantic cod, 272

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lacks the entire machinery of MHC class II–related antigen presentation and the CD4 coreceptordistinguishing helper T cell lineages in mammals. By way of compensation, increased numbers of MHC class I genes and genes encoding TLR-like pattern-recognition receptors are present in the genome, indicating possible ways of overcoming the lack of a seemingly indispensable—as judged from the mammalian perspective—aspect of immune surveillance of exogenous antigens (134). Such observations are important for our understanding of the pathophysiological consequences of failing immune functions and hence for the development of nonintuitive, novel treatment strategies that go beyond the mere repair of faulty immune-response capacities. An additional aspect emerging from comparative studies is the apparent stepwise emergence of lymphocyte sublineages. Recent work on lampreys, for instance, has indicated that basal vertebrates already possess the two principal lymphocyte lineages, namely, antibody-producing B cells and T-like cells (2). There are even indications for the presence of two T cell lineages, one expressing the VLRA receptor and another the VLRC receptor, perhaps akin to the two major T cell lineages of jawed vertebrates, as defined by the expression of ab TCR and gd TCR (69). So far unresolved, however, is the question of whether basal vertebrates also possess the multiple sublineages of T cells that characterize the mammalian immune system; this is particularly relevant for the many CD4þ helper cell types (135) (Figure 8). Considering that antibody responses in basal vertebrates appear to be less vigorous than in tetrapods (136), and thus perhaps indicative of weak T cell help, it is conceivable that the underlying cellular interactions are less well developed; this conclusion is supported by the paucity of secondary lymphoid

a

CD8+ cytotoxic lineage

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MHC: major histocompatibility complex

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CD4+

ers Induc

TH1

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Figure 8 T cell lineages in mammals. T cells expressing the ab T cell receptor (TCR) are divided into two general categories: the cytotoxic T cells expressing the coreceptor CD8 and recognizing antigenic peptides in the context of MHC class I (MHCI), and the helper T cells, expressing the CD4 coreceptor and recognizing antigens only when presented by MHC class II (MHCII). For CD4þ T cell lineages, several sublineages are known, each induced by a unique combination of effector cytokines and interleukins and supported by the activity of specific transcription factors. For instance, the phenotype of regulatory T cells (Treg) is induced by TGFb and stabilized by the transcription factor FOXP3. To date, it is unknown whether an equivalent subdifferentiation occurs in the T cell compartments of bony and cartilaginous fishes and jawless vertebrates. Abbreviation: APC, antigen-presenting cell.

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tissues and their less complex morphological structure (37, 137). One potential strategy for examining this problem will be afforded by the imminent completion of genome-sequencing projects for many basal vertebrates. In this context, the genome analysis of cartilaginous fishes will be key to evaluating the extent of lineage diversification at the outset of jawed vertebrate evolution, with direct relevance to guiding studies on the degree of lineage differentiation in jawless vertebrates. Not only are the observations pertaining to the presence of alternative strategies of immune system organization interesting in their own right, it might even be possible to harness these strategies for medical purposes. In particular, a more thorough understanding of the genetic network structures underlying the development of immune responses might lead to the therapeutic exploitation of genetic interactions aimed at the alleviation and treatment of various kinds of immune deficiencies (13, 14).

THE REGULATION OF IMMUNE RESPONSES A particularly interesting aspect of immune system function is the presence of regulatory lymphocytes (138). In mammals, arguably the most important of such lymphocytes are the Foxp3þ regulatory T cells of the CD4 lineage (139). Previously, it was reported that functionally important amino acid residues in the DNA-binding domain of mammalian FOXP3 are not present in FOXP3 homologs of evolutionarily older vertebrates, suggesting that the role of FOXP3 in the immune system of fishes is different from that played in the immune system of placental vertebrates (140). Hence, the immunological phenotype of fishes carrying an inactivated Foxp3 gene will be particularly important for testing various hypotheses related to immune regulation in lower vertebrates. In this context, it is interesting to note that recent studies have revealed a differential requirement of the thymic medulla for conventional CD4þ and regulatory CD4þFoxp3þ cells; Cowan et al. (141) established that CD4þ cell development does not depend on an intact medullary compartment, suggesting that the complex microenvironment required for the generation of Foxp3þ regulatory T cells might have coevolved with the facility of dominant immune regulation. Although the precise cellular and molecular hallmarks of immune regulatory mechanisms likely have changed over evolutionary time and thus differ in fishes and in mammals, at least some immune effector molecules might be conserved. For instance, homologs of the key proinflammatory cytokine IL17 are basic components of the chordate genome (142); likewise, IL10, which is a key anti-inflammatory cytokine in mammals (143), is present in basal jawed vertebrates (Figure 9). Hence, at least some components of the tool kit required for immune regulation apparently are deeply rooted in chordate phylogeny.

NOVEL INSIGHTS INTO IMMUNE FUNCTIONS PROVIDED BY LOWER VERTEBRATES Most of the information regarding the function of adaptive immune systems has been obtained from the traditional targets of immunological research, such as humans, rodents, birds, and amphibians. In recent years, genetically tractable fish species have contributed significantly to our understanding of immune functions. For instance, the unique advantages afforded by live imaging in zebrafish (144), combined with facile means of genetic and pharmacological interference, have provided novel insights into the pathogenesis of mycobacterial infection (145). Recent findings in zebrafish models highlight evolutionarily conserved pathways of hematopoietic development (36, 146) and provide new experimental systems for allogeneic transplantations (147) and genetic and chemical screens (13). 274

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DNHSCQFLKEMLNFYLTDVIPAAKTHSRVINVSVSKIGNAL GRLGCQFLKEMLDFYLSHIIPAAKTQSKAYNTHISKIGNTL GYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENL

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Figure 9 Presence of the anti-inflammatory cytokine IL10 in cartilaginous fishes. Comparison of conceptually translated partial genomic sequences for IL10 genes from Leucoraja erinacea (contig 9419 retrieved from http:// skatebase.org/ContigLookup) and Callorhinchus milii (Genbank accession no. AAVX01450757.1) to the equivalent region of the human IL10 protein (residues 76–116; Genbank accession no. CAG46790) is shown; identical residues are colored.

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WHAT CONSTITUTES AN ADAPTIVE IMMUNE SYSTEM? Immunologists generally distinguish innate immunity from adaptive immunity. In the classical definition, innate immune responses are stereotyped, meaning that a secondary response is no different from the first. By contrast, an immune response is said to be adaptive when effector cells assume a state of altered memory, allowing more vigorous responses during secondary encounters with the same antigen. Likewise, innate immune responses were thought to occur without eliciting cell proliferation or clonal expansion, two hallmarks of the lymphocyte adaptive response. However, recent work has blurred the sharp distinction between innate and adaptive immunity based on the aforementioned criterion of immunological memory. In vertebrates, the functional characteristics of natural killer (NK) cells provide an instructive example (148). NK cells are equipped with different combinations of activating and inhibiting receptors (149). During an infection, NK cells become differentially activated and proliferate upon antigen encounter, in a manner akin to the clonal activation of adaptive lymphocytes; the activated NK cells then transit into a kind of memory state, which endows them with the capacity of enhanced cytolytic function and cytokine production upon reinfection (150). Hence, the general features of NK immunity resemble the classical adaptive signature. Moreover, experiments with invertebrates demonstrated that infection often leads to increased, sometimes even cross-protecting, resistance against pathogens other than those eliciting the primary response in various invertebrates (151). Hence, in addition to a bona fide adaptive response, variant forms of immunological memory exist (e.g., trained immunity) (152). Interestingly, adaptive immunity is not restricted to multicellular organisms but can also be found in unicellular organisms. For archaea and bacteria, horizontal gene transfer is an important mechanism by which prokaryotes acquire new traits that are beneficial in a continuously changing environment; however, acquisition of foreign DNA can also have detrimental effects (153). One way of protecting against foreign DNA is exemplified by the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas (CRISPR-associated) system, which generates resistance against invading nucleic acids (154–157) but also regulates the interaction of bacteria and eukaryotic hosts (158). A detailed discussion of the complexities of CRISPR/Cas systems is beyond the scope of this review; however, they all share the same general property of incorporating parts of foreign DNA into their genome, in such a way that an infection leaves a permanent trace in the host genome. These foreign sequences become incorporated into so-called CRISPR RNAs (crRNAs) encompassing unique sequences complementary to target sequences. Complexes consisting of crRNAs and target sequences are recognized by Cas proteins that mediate target destruction. Hence, after infection, the endogenous CRISPR locus (Figure 10, left) becomes extended by incorporation of foreign DNA (Figure 10, center), affording the possibility of generating targetspecific crRNAs. Together with the Cas protein, these newly acquired crRNAs mediate resistance to repeated intrusion of foreign DNA (Figure 10, right). The CRISPR/Cas system exemplifies how even unicellular organisms can achieve a memory state that allows a qualitatively different adaptive response upon secondary infection. www.annualreviews.org



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Guide RNAs

Before infection

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Second infection

Figure 10 An adaptive immune system in prokaryotes. The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR-associated) system generates resistance against invading nucleic acids by generating sequence-specific CRISPR RNAs (crRNAs) that represent sequences complementary to various target sequences. When infection by a bacteriophage occurs, the endogenous CRISPR locus becomes modified by incorporation of foreign DNA fragments (orange), allowing the system to produce a novel type of crRNA. Upon reinfection with the same bacteriophage, the foreign DNA is detected by a target-specific crRNA and degraded by the Cas protein. In this manner, unicellular organisms can achieve a memory state that allows a targeted response upon secondary infection.

If the presence of immunological memory as such can no longer be considered a unique feature of adaptive immunity, are there other features that allow the distinction between adaptive and innate immunity? The unique characteristic of vertebrate lymphocytes is their clonal expression of somatically diversified antigen receptors, which, to a first approximation, all possess different antigen specificities. This is in contrast to all other types of immune effector cells, which express only germline-encoded antigen receptors, albeit sometimes in clonally variegated fashion. Because of the resulting enormous (almost limitless) structural diversity of Igs, TCRs, and the various types of VLRs, adaptive immunity invariably requires a means to restrict self-reactivity arising from the quasi-random specificities of these antigen receptors. To be useful, this quality control must be spatially and temporally coupled to the formation of the repertoire; primary lymphoid organs in vertebrates, such as the thymus, serve this end.

CONCLUSIONS The past several years have seen a major leap in our understanding of the evolutionary trajectory of adaptive immunity. It has become apparent that many aspects of an adaptive immune response, such as memory of past encounters, emerged before the appearance of vertebrates, some even in prokaryotes. However, vertebrates are distinguished by unique innovations, for instance, the clonal expression of somatically diversifying antigen receptors on lymphocytes. Interestingly, the two major groups of vertebrates employ distinct types of molecules for antigen recognition and also rely on two different principal mechanisms of antigen receptor gene diversification. These unexpected discoveries provide a glimpse into the early stages of vertebrate evolution and into the structure of the immune system of the ancestor common to jawless and jawed vertebrates. Analyses of the genomes of many additional vertebrate species promise to reveal unprecedented insights into group-specific and species-specific aspects of adaptive immunity.

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SUMMARY POINTS 1. Lymphoid organs are distinguished by a characteristic apposition of distinct stromal cell types and hematopoietic cells. 2. The thymus is a vertebrate-specific innovation and serves as a primary lymphoid organ for the development of T cells. 3. Lymph nodes are a modern innovation of vertebrate immune systems. 4. All vertebrate lymphocytes clonally express somatically diversified antigen receptors. 5. Jawless vertebrates employ leucine-rich-repeat-containing antigen receptors, whereas the B and T cell receptors of jawed vertebrates are encoded by distinct members of the immunoglobulin supergene family. 6. The evolution of somatic diversification of antigen receptors might have favored complex mutualistic interactions between vertebrates and their microbiome. 7. Several aspects of adaptive immune responses, such as memory formation, evolved before the emergence of vertebrates.

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.

ACKNOWLEDGMENT Work in the authors’ laboratory is supported by the Max Planck Society. LITERATURE CITED 1. Pancer Z, Amemiya CT, Ehrhardt GRA, Ceitlin J, Gartland GL, Cooper MD. 2004. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430:174–80 2. Guo P, Hirano M, Herrin BR, Li J, Yu C, et al. 2009. Dual nature of the adaptive immune system in lampreys. Nature 459:796–801 3. Flajnik MF, Du Pasquier L. 2004. Evolution of innate and adaptive immunity: Can we draw a line? Trends Immunol. 25:640–44 4. Pancer Z, Cooper MD. 2006. The evolution of adaptive immunity. Annu. Rev. Immunol. 24:497–518 5. Cooper MD, Alder MN. 2006. The evolution of adaptive immune systems. Cell 124:815–22 6. Du Pasquier L. 2005. Meeting the demand for innate and adaptive immunities during evolution. Scand. J. Immunol. 62(Suppl. 1):39–48 7. Litman GW, Rast JP, Fugmann SD. 2010. The origins of vertebrate adaptive immunity. Nat. Rev. Immunol. 10:543–53 8. Flajnik MF, Kasahara M. 2010. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11:47–59 9. Herrin BR, Cooper MD. 2010. Alternative adaptive immunity in jawless vertebrates. J. Immunol. 185:1367–74 10. Cooper MD, Herrin BR. 2010. How did our complex immune system evolve? Nat. Rev. Immunol. 10:2–3 11. Boehm T. 2011. Design principles of adaptive immune systems. Nat. Rev. Immunol. 11:307–17

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Annual Review of Animal Biosciences Volume 2, 2014

Contents

Annu. Rev. Anim. Biosci. 2014.2:259-283. Downloaded from www.annualreviews.org by University of California - San Diego on 09/14/14. For personal use only.

From Germ Cell Preservation to Regenerative Medicine: An Exciting Research Career in Biotechnology Ian Wilmut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Genomic Imprinting in Farm Animals Xiuchun (Cindy) Tian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Recent Advances in Primate Phylogenomics Jill Pecon-Slattery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Domestication Genomics: Evidence from Animals Guo-Dong Wang, Hai-Bing Xie, Min-Sheng Peng, David Irwin, and Ya-Ping Zhang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Behavior Genetics and the Domestication of Animals Per Jensen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Applied Animal Genomics: Results from the Field Alison L. Van Eenennaam, Kent A. Weigel, Amy E. Young, Matthew A. Cleveland, and Jack C.M. Dekkers . . . . . . . . . . . . . . . . . . . . 105 Pestiviruses Matthias Schweizer and Ernst Peterhans . . . . . . . . . . . . . . . . . . . . . . . . . 141 Pathogenesis and Molecular Biology of a Transmissible Tumor in the Tasmanian Devil Hannah S. Bender, Jennifer A. Marshall Graves, and Janine E. Deakin . . . 165 Animal Models of Bovine Leukemia Virus and Human T-Lymphotrophic Virus Type-1: Insights in Transmission and Pathogenesis Michael D. Lairmore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Malignant Catarrhal Fever: Inching Toward Understanding Hong Li, Cristina W. Cunha, Naomi S. Taus, and Donald P. Knowles . . . 209

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Comparative Immune Systems in Animals Shaochun Yuan, Xin Tao, Shengfeng Huang, Shangwu Chen, and Anlong Xu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Origin and Evolution of Adaptive Immunity Thomas Boehm and Jeremy B. Swann . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

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The Functional Significance of Cattle Major Histocompatibility Complex Class I Genetic Diversity Shirley A. Ellis and John A. Hammond . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Incidence of Abnormal Offspring from Cloning and Other Assisted Reproductive Technologies Jonathan R. Hill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 Preadipocyte and Adipose Tissue Differentiation in Meat Animals: Influence of Species and Anatomical Location G.J. Hausman, U. Basu, S. Wei, D.B. Hausman, and M.V. Dodson . . . . . 323 Serotonin: A Local Regulator in the Mammary Gland Epithelium Nelson D. Horseman and Robert J. Collier . . . . . . . . . . . . . . . . . . . . . . . 353 Evolution of the Modern Broiler and Feed Efficiency Paul B. Siegel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375 Amino Acid Nutrition in Animals: Protein Synthesis and Beyond Guoyao Wu, Fuller W. Bazer, Zhaolai Dai, Defa Li, Junjun Wang, and Zhenlong Wu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 The Suckling Piglet as an Agrimedical Model for the Study of Pediatric Nutrition and Metabolism Jack Odle, Xi Lin, Sheila K. Jacobi, Sung Woo Kim, and Chad H. Stahl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Cattle Production Systems: Ecology of Existing and Emerging Escherichia coli Types Related to Foodborne Illness David R. Smith . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Gastrointestinal Tract Microbiota and Probiotics in Production Animals Carl J. Yeoman and Bryan A. White . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Biodiversity of Cone Snails and Other Venomous Marine Gastropods: Evolutionary Success Through Neuropharmacology Baldomero M. Olivera, Patrice Showers Corneli, Maren Watkins, and Alexander Fedosov . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487 Ecological Risk Analysis and Genetically Modified Salmon: Management in the Face of Uncertainty Darek T.R. Moreau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Contents

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The Modern Feedlot for Finishing Cattle John J. Wagner, Shawn L. Archibeque, and Dillon M. Feuz . . . . . . . . . . . 535 The Nexus of Environmental Quality and Livestock Welfare Sara E. Place and Frank M. Mitloehner . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Errata

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An online log of corrections to Annual Review of Animal Biosciences articles may be found at http://www.annualreviews.org/errata/animal

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Contents

Annual Reviews It’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org

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Editor: Stephen E. Fienberg, Carnegie Mellon University

Associate Editors: Nancy Reid, University of Toronto Stephen M. Stigler, University of Chicago The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as well as all scientists and users of statistics about major methodological advances and the computational tools that allow for their implementation. It will include developments in the field of statistics, including theoretical statistical underpinnings of new methodology, as well as developments in specific application domains such as biostatistics and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015. table of contents:

• What Is Statistics? Stephen E. Fienberg • A Systematic Statistical Approach to Evaluating Evidence from Observational Studies, David Madigan, Paul E. Stang, Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage, Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema, Patrick B. Ryan

• High-Dimensional Statistics with a View Toward Applications in Biology, Peter Bühlmann, Markus Kalisch, Lukas Meier • Next-Generation Statistical Genetics: Modeling, Penalization, and Optimization in High-Dimensional Data, Kenneth Lange, Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

• The Role of Statistics in the Discovery of a Higgs Boson, David A. van Dyk

• Breaking Bad: Two Decades of Life-Course Data Analysis in Criminology, Developmental Psychology, and Beyond, Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

• Brain Imaging Analysis, F. DuBois Bowman

• Event History Analysis, Niels Keiding

• Statistics and Climate, Peter Guttorp

• Statistical Evaluation of Forensic DNA Profile Evidence, Christopher D. Steele, David J. Balding

• Climate Simulators and Climate Projections, Jonathan Rougier, Michael Goldstein • Probabilistic Forecasting, Tilmann Gneiting, Matthias Katzfuss • Bayesian Computational Tools, Christian P. Robert • Bayesian Computation Via Markov Chain Monte Carlo, Radu V. Craiu, Jeffrey S. Rosenthal • Build, Compute, Critique, Repeat: Data Analysis with Latent Variable Models, David M. Blei • Structured Regularizers for High-Dimensional Problems: Statistical and Computational Issues, Martin J. Wainwright

• Using League Table Rankings in Public Policy Formation: Statistical Issues, Harvey Goldstein • Statistical Ecology, Ruth King • Estimating the Number of Species in Microbial Diversity Studies, John Bunge, Amy Willis, Fiona Walsh • Dynamic Treatment Regimes, Bibhas Chakraborty, Susan A. Murphy • Statistics and Related Topics in Single-Molecule Biophysics, Hong Qian, S.C. Kou • Statistics and Quantitative Risk Management for Banking and Insurance, Paul Embrechts, Marius Hofert

Access this and all other Annual Reviews journals via your institution at www.annualreviews.org.

Annual Reviews | Connect With Our Experts Tel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]

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The evolutionary emergence of vertebrates was accompanied by major morphological and functional innovations, including the development of an adaptive ...
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