Review Article | Published:

A cold-blooded view of adaptive immunity

Nature Reviews Immunologyvolume 18pages438453 (2018) | Download Citation


The adaptive immune system arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the adaptive immune system has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an adaptive immune system in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the adaptive immune system.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Janeway, C. A. Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13, 11–16 (1992).

  2. 2.

    Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

  3. 3.

    Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

  4. 4.

    Cooper, M. D., Raymond, D. A., Peterson, R. D., South, M. A. & Good, R. A. The functions of the thymus system and the bursa system in the chicken. J. Exp. Med. 123, 75–102 (1966).

  5. 5.

    Klein, J. & Figueroa, F. Evolution of the major histocompatibility complex. Crit. Rev. Immunol. 6, 295–386 (1986).

  6. 6.

    Pancer, Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004). This study presents the discovery of the lamprey antigen receptors, which were generated somatically and expressed clonally, and a member of the LRR family.

  7. 7.

    Flajnik, M. F., Deschacht, N. & Muyldermans, S. A case of convergence: why did a simple alternative to canonical antibodies arise in sharks and camels? PLoS Biol. 9, e1001120 (2011).

  8. 8.

    Flajnik, M. F. & Du Pasquier, L. in Fundamental Immunology (ed. William Paul, E.) 56–124 (Lipponcott Williams & Wilkins, Philadelphia, PA, 2008).

  9. 9.

    Morales Poole, J. R., Paganini, J. & Pontarotti, P. Convergent evolution of the adaptive immune response in jawed vertebrates and cyclostomes: an evolutionary biology approach based study. Dev. Comp Immunol. 75, 120–126 (2017).

  10. 10.

    Schluter, S. F., Bernstein, R. M., Bernstein, H. & Marchalonis, J. J. ‘Big Bang’ emergence of the combinatorial immune system. Dev. Comp. Immunol. 23, 107–111 (1999). This paper describes the rapid evolutionary appearance of most elements of the adaptive immune response.

  11. 11.

    Guo, P. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009). This study demonstrates that the emergence of T cells and B cells preceded the divergence of antigen receptors into two separate gene families.

  12. 12.

    Flajnik, M. F. Re-evaluation of the immunological Big Bang. Curr. Biol. 24, R1060–R1065 (2014).

  13. 13.

    Tacchi, L., Larragoite, E. T., Munoz, P., Amemiya, C. T. & Salinas, I. African lungfish reveal the evolutionary origins of organized mucosal lymphoid tissue in vertebrates. Curr. Biol. 25, 2417–2424 (2015).

  14. 14.

    Flajnik, M. F. All GOD’s creatures got dedicated mucosal immunity. Nat. Immunol. 11, 777–779 (2010).

  15. 15.

    Xu, Z. et al. Mucosal immunoglobulins at respiratory surfaces mark an ancient association that predates the emergence of tetrapods. Nat. Commun. 7, 10728 (2016). This work describes the emergence of mucosal secondary lymphoid tissues.

  16. 16.

    Malmstrom, M. et al. Evolution of the immune system influences speciation rates in teleost fishes. Nat. Genet. 48, 1204–1210 (2016).

  17. 17.

    Star, B. et al. The genome sequence of Atlantic cod reveals a unique immune system. Nature 477, 207–210 (2011). This study shows that MHC class II and associated molecules are lost in the teleost Atlantic cod.

  18. 18.

    Hinds, K. R. & Litman, G. W. Major reorganization of immunoglobulin VH segmental elements during vertebrate evolution. Nature 320, 546–549 (1986). This study presents the discovery of the cluster-type immunoglobulin gene organization in cartilaginous fish, which is likely primordial.

  19. 19.

    Hsu, E. Assembly and expression of shark Ig genes. J. Immunol. 196, 3517–3523 (2016).

  20. 20.

    Yoder, J. A. & Litman, G. W. The phylogenetic origins of natural killer receptors and recognition: relationships, possibilities, and realities. Immunogenetics 63, 123–141 (2011). This is an excellent review detailing the difficulty in identifying NKR throughout the vertebrate tree owing to rapid NKR evolution.

  21. 21.

    Ohta, Y., Goetz, W., Hossain, M. Z., Nonaka, M. & Flajnik, M. F. Ancestral organization of the MHC revealed in the amphibian. Xenopus. J. Immunol. 176, 3674–3685 (2006).

  22. 22.

    Kaufman, J. et al. The chicken B locus is a minimal essential major histocompatibility complex. Nature 401, 923–925 (1999).

  23. 23.

    McConnell, S. C. et al. Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution. Proc. Natl Acad. Sci. USA 113, E5014–E5023 (2016).

  24. 24.

    Ohta, Y. & Flajnik, M. F. Coevolution of MHC genes (LMP/TAP/class Ia, NKT-class Ib, NKp30-B7H6): lessons from cold-blooded vertebrates. Immunol. Rev. 267, 6–15 (2015).

  25. 25.

    Chappell, P. et al. Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding. eLife 4, e05345 (2015).

  26. 26.

    Flajnik, M. F. Comparative analyses of immunoglobulin genes: surprises and portents. Nat. Rev. Immunol. 2, 688–698 (2002). This review details the evolution of the antibody system prior to 2002, most of which is not described in the present Review.

  27. 27.

    Boehm, T., Hess, I. & Swann, J. B. Evolution of lymphoid tissues. Trends Immunol. 33, 315–321 (2012).

  28. 28.

    Neely, H. R. & Flajnik, M. F. Emergence and evolution of secondary lymphoid organs. Annu. Rev. Cell Dev. Biol. 32, 693–711 (2016).

  29. 29.

    Wilson, M. et al. What limits affinity maturation of antibodies in Xenopus—the rate of somatic mutation or the ability to select mutants? EMBO J. 11, 4337–4347 (1992). This work proposes that somatic hypermutation per se is not the driving force in affinity maturation; rather, it is the lack of ‘selecting environments’.

  30. 30.

    Zapata, A. & Amemiya, C. T. Phylogeny of lower vertebrates and their immunological structures. Curr. Top. Microbiol. Immunol. 248, 67–107 (2000).

  31. 31.

    Williams, A. F. & Barclay, A. N. The immunoglobulin superfamily — domains for cell surface recognition. Annu. Rev. Immunol. 6, 381–405 (1988).

  32. 32.

    Sakano, H., Huppi, K., Heinrich, G. & Tonegawa, S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280, 288–294 (1979).

  33. 33.

    Flajnik, M. F. Evidence of G.O.D.’s miracle: unearthing a RAG transposon. Cell 166, 11–12 (2016).

  34. 34.

    Du Pasquier, L., Zucchetti, I. & DeSantis, R. Immunoglobulin superfamily receptors in protochordates: before RAG time. Immunol. Rev. 198, 233–248 (2004).

  35. 35.

    Rogozin, I. B. et al. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat. Immunol. 8, 647–656 (2007). This study presents the discovery of two novel lamprey APOBEC family members, CDA1 and CDA2, implicated in generation of VLR diversity.

  36. 36.

    Finstad, J. & Good, R. A. The evolution of the immune response. 3. Immunologic responses in the lamprey. J. Exp. Med. 120, 1151–1168 (1964).

  37. 37.

    McCurley, N., Hirano, M., Das, S. & Cooper, M. D. Immune related genes underpin the evolution of adaptive immunity in jawless vertebrates. Curr. Genom. 13, 86–94 (2012).

  38. 38.

    Ishiguro, H. et al. Isolation of a hagfish gene that encodes a complement component. EMBO J. 11, 829–837 (1992). This work puts the final ‘nail in the coffin’ for potential discovery of immunoglobulin, TCR and MHC in agnathans.

  39. 39.

    Herrin, B. R. et al. Structure and specificity of lamprey monoclonal antibodies. Proc. Natl Acad. Sci. USA 105, 2040–2045 (2008).

  40. 40.

    Alder, M. N. et al. Antibody responses of variable lymphocyte receptors in the lamprey. Nat. Immunol. 9, 319–327 (2008).

  41. 41.

    Hirano, M. et al. Evolutionary implications of a third lymphocyte lineage in lampreys. Nature 501, 435–438 (2013). This study presents a third lineage of lamprey antigen receptor, VLRC, which is likely similar to gnathostome γδ T cells.

  42. 42.

    Marchalonis, J. & Edelman, G. M. Polypeptide chains of immunoglobulins from the smooth dogfish (Mustelus canis). Science 154, 1567–1568 (1966).

  43. 43.

    Clem, I. W., De, B. F. & Sigel, M. M. Phylogeny of immunoglobulin structure and function. II. Immunoglobulins of the nurse shark. J. Immunol. 99, 1226–1235 (1967).

  44. 44.

    Dooley, H. & Flajnik, M. F. Shark immunity bites back: affinity maturation and memory response in the nurse shark, Ginglymostoma cirratum. Eur. J. Immunol. 35, 936–945 (2005).

  45. 45.

    Castro, C. D. & Flajnik, M. F. Putting J chain back on the map: how might its expression define plasma cell development? J. Immunol. 193, 3248–3255 (2014).

  46. 46.

    Ravi, V. & Venkatesh, B. Rapidly evolving fish genomes and teleost diversity. Curr. Opin. Genet. Dev. 18, 544–550 (2008). This study demonstrates rapid expansions and contractions of bony fish genomes.

  47. 47.

    Hohman, V. S. et al. J chain in the nurse shark: implications for function in a lower vertebrate. J. Immunol. 170, 6016–6023 (2003).

  48. 48.

    Ye, J., Bromage, E. S. & Kaattari, S. L. The strength of B cell interaction with antigen determines the degree of IgM polymerization. J. Immunol. 184, 844–850 (2010). This work suggests that a form of affinity maturation in teleosts can be achieved at the level of the biochemistry of multimeric IgM.

  49. 49.

    Wilson, M. R. et al. The immunoglobulin M heavy chain constant region gene of the channel catfish, Ictalurus punctatus: an unusual mRNA splice pattern produces the membrane form of the molecule. Nucleic Acids Res. 18, 5227–5233 (1990).

  50. 50.

    Ohta, Y. & Flajnik, M. IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc. Natl Acad. Sci. USA 103, 10723–10728 (2006). This study shows that IgD is present throughout the gnathostomes and is quite plastic in structure and likely in function.

  51. 51.

    Edholm, E. S., Bengten, E. & Wilson, M. Insights into the function of IgD. Dev. Comp. Immunol. 35, 1309–1316 (2011).

  52. 52.

    Wilson, M. et al. A novel chimeric Ig heavy chain from a teleost fish shares similarities to IgD. Proc. Natl Acad. Sci. USA 94, 4593–4597 (1997).

  53. 53.

    Zhao, Y. et al. Identification of IgF, a hinge-region-containing Ig class, and IgD in Xenopus tropicalis. Proc. Natl Acad. Sci. USA 103, 12087–12092 (2006).

  54. 54.

    Greenberg, A. S. et al. A novel “chimeric” antibody class in cartilaginous fish: IgM may not be the primordial immunoglobulin. Eur. J. Immunol. 26, 1123–1129 (1996).

  55. 55.

    Berstein, R. M., Schluter, S. F., Shen, S. & Marchalonis, J. J. A new high molecular weight immunoglobulin class from the carcharhine shark: implications for the properties of the primordial immunoglobulin. Proc. Natl Acad. Sci. USA 93, 3289–3293 (1996).

  56. 56.

    Ota, T., Rast, J. P., Litman, G. W. & Amemiya, C. T. Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype within the Dipnoi reveals an evolutionary paradox. Proc. Natl Acad. Sci. USA 100, 2501–2506 (2003).

  57. 57.

    Amemiya, C. T. et al. The African coelacanth genome provides insights into tetrapod evolution. Nature 496, 311–316 (2013). This study demonstrates a loss of IgM in coelacanths and the likely takeover of function by IgD and/or IgW genes.

  58. 58.

    Saha, N. R. et al. Genome complexity in the coelacanth is reflected in its adaptive immune system. J. Exp. Zool. B Mol. Dev. Evol. 322, 438–463 (2014).

  59. 59.

    Chen, K. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat. Immunol. 10, 889–898 (2009).

  60. 60.

    Edholm, E. S. et al. Identification of two IgD +  B cell populations in channel catfish, Ictalurus punctatus. J. Immunol. 185, 4082–4094 (2010).

  61. 61.

    Leslie, G. A. & Clem, L. W. Phylogeny of immunoglobulin structure and function. 3. Immunoglobulins of the chicken. J. Exp. Med. 130, 1337–1352 (1969).

  62. 62.

    Martin, S. W. & Goodnow, C. C. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat. Immunol. 3, 182–188 (2002).

  63. 63.

    Chen, X. et al. How B cells remember? A sophisticated cytoplasmic tail of mIgG is pivotal for the enhanced transmembrane signaling of IgG-switched memory B cells. Prog. Biophys. Mol. Biol. 118, 89–94 (2015).

  64. 64.

    Pettinello, R. & Dooley, H. The immunoglobulins of cold-blooded vertebrates. Biomolecules 4, 1045–1069 (2014).

  65. 65.

    Bengten, E. & Wilson, M. Antibody repertoires in fish. Results Probl. Cell Differ. 57, 193–234 (2015).

  66. 66.

    Mashoof, S. & Criscitiello, M. F. Fish immunoglobulins. Biology 5, 45 (2016).

  67. 67.

    Criscitiello, M. F. & Flajnik, M. F. Four primordial immunoglobulin light chain isotypes, including lambda and kappa, identified in the most primitive living jawed vertebrates. Eur. J. Immunol. 37, 2683–2694 (2007). This work definitively demonstrates that λ and κ genes emerged in the earliest gnathostomes and that σ L chain genes are found throughout the ectotherms.

  68. 68.

    Edholm, E. S., Wilson, M. & Bengten, E. Immunoglobulin light (IgL) chains in ectothermic vertebrates. Dev. Comp. Immunol. 35, 906–915 (2011).

  69. 69.

    Schwager, J., Burckert, N., Schwager, M. & Wilson, M. Evolution of immunoglobulin light chain genes: analysis of Xenopus IgL isotypes and their contribution to antibody diversity. EMBO J. 10, 505–511 (1991).

  70. 70.

    Anderson, M. K., Shamblott, M. J., Litman, R. T. & Litman, G. W. Generation of immunoglobulin light chain gene diversity in Raja erinacea is not associated with somatic rearrangement, an exception to a central paradigm of B cell immunity. J. Exp. Med. 182, 109–119 (1995).

  71. 71.

    Lee, S. S., Tranchina, D., Ohta, Y., Flajnik, M. F. & Hsu, E. Hypermutation in shark immunoglobulin light chain genes results in contiguous substitutions. Immunity 16, 571–582 (2002).

  72. 72.

    Hsu, E., Lefkovits, I., Flajnik, M. & Du, P. L. Light chain heterogeneity in the amphibian. Xenopus. Mol. Immunol. 28, 985–994 (1991).

  73. 73.

    Zhang, N. et al. Preferential combination between the light and heavy chain isotypes of fish immunoglobulins. Dev. Comp. Immunol. 61, 169–179 (2016).

  74. 74.

    Rast, J. P. et al. Immunoglobulin light chain class multiplicity and alternative organizational forms in early vertebrate phylogeny. Immunogenetics 40, 83–99 (1994).

  75. 75.

    Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).

  76. 76.

    Iacoangeli, A. et al. Evidence for Ig light chain isotype exclusion in shark B lymphocytes suggests ordered mechanisms. J. Immunol. 199, 1875–1885 (2017).

  77. 77.

    Rast, J. P. et al. alpha, beta, gamma, and delta T cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 6, 1–11 (1997). This paper shows that all mammalian TCR genes are present in cartilaginous fish, which was previously doubted by many investigators.

  78. 78.

    Criscitiello, M. F., Ohta, Y., Saltis, M., McKinney, E. C. & Flajnik, M. F. Evolutionarily conserved TCR binding sites, identification of T cells in primary lymphoid tissues, and surprising trans-rearrangements in nurse shark. J. Immunol. 184, 6950–6960 (2010).

  79. 79.

    Horton, J. D. et al. T-cell and natural killer cell development in thymectomized. Xenopus. Immunol. Rev. 166, 245–258 (1998).

  80. 80.

    Leal, E., Granja, A. G., Zarza, C. & Tafalla, C. Distribution of T cells in rainbow trout (Oncorhynchus mykiss) skin and responsiveness to viral infection. PLoS ONE. 11, e0147477 (2016).

  81. 81.

    Fischer, U., Koppang, E. O. & Nakanishi, T. Teleost T and NK cell immunity. Fish Shellfish Immunol. 35, 197–206 (2013).

  82. 82.

    Castro, R., Navelsaker, S., Krasnov, A., Du Pasquier, L. & Boudinot, P. Describing the diversity of Ag specific receptors in vertebrates: contribution of repertoire deep sequencing. Dev. Comp Immunol. 75, 28–37 (2017).

  83. 83.

    Saito, H. et al. Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. Nature 309, 757–762 (1984).

  84. 84.

    Chien, Y. H., Iwashima, M., Kaplan, K. B., Elliott, J. F. & Davis, M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. Nature 327, 677–682 (1987).

  85. 85.

    Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

  86. 86.

    Criscitiello, M. F., Saltis, M. & Flajnik, M. F. An evolutionarily mobile antigen receptor variable region gene: doubly rearranging NAR-TcR genes in sharks. Proc. Natl Acad. Sci. USA 103, 5036–5041 (2006). This is the first paper to demonstrate that IgV elements can contribute directly to the TCRδ repertoire.

  87. 87.

    Parra, Z. E., Lillie, M. & Miller, R. D. A model for the evolution of the mammalian t-cell receptor alpha/delta and mu loci based on evidence from the duckbill Platypus. Mol. Biol. Evol. 29, 3205–3214 (2012). This study shows that IgVH elements associated with TCR Cδ chain elements are common in all vertebrates except bony fish and placental mammals.

  88. 88.

    Venkatesh, B. et al. Elephant shark genome provides unique insights into gnathostome evolution. Nature 505, 174–179 (2014).

  89. 89.

    Parra, Z. E., Ohta, Y., Criscitiello, M. F., Flajnik, M. F. & Miller, R. D. The dynamic TCRdelta: TCRdelta chains in the amphibian Xenopus tropicalis utilize antibody-like V genes. Eur. J. Immunol. 40, 2319–2329 (2010). This study suggests that a cis duplication gave rise to IgH and/or IgL and TCR σδ loci early in gnathostome evolution.

  90. 90.

    Glusman, G. et al. Comparative genomics of the human and mouse T cell receptor loci. Immunity 15, 337–349 (2001).

  91. 91.

    Rock, E. P., Sibbald, P. R., Davis, M. M. & Chien, Y. H. CDR3 length in antigen-specific immune receptors. J. Exp. Med. 179, 323–328 (1994).

  92. 92.

    Zeng, X. et al. Gammadelta T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity 37, 524–534 (2012).

  93. 93.

    Ravens, S. et al. Human gammadelta T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection. Nat. Immunol. 18, 393–401 (2017).

  94. 94.

    Chen, H., Bernstein, H., Ranganathan, P. & Schluter, S. F. Somatic hypermutation of TCR gamma V genes in the sandbar shark. Dev. Comp. Immunol. 37, 176–183 (2012). This study presents somatic hypermutation of TCRγ genes in sharks.

  95. 95.

    Agrawal, A., Eastman, Q. M. & Schatz, D. G. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394, 744–751 (1998). This study demonstrates the transposition of DNA in vitro by RAG1 and/or RAG2, providing a model for the RAG transposon movement into and IgSF gene early in vertebrate evolution.

  96. 96.

    Carmona, L. M. & Schatz, D. G. New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination. FEBS J. 284, 1590–1605 (2017).

  97. 97.

    Carmona, L. M., Fugmann, S. D. & Schatz, D. G. Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination. Genes Dev. 30, 909–917 (2016).

  98. 98.

    Morales Poole, J. R., Huang, S. F., Xu, A., Bayet, J. & Pontarotti, P. The RAG transposon is active through the deuterostome evolution and domesticated in jawed vertebrates. Immunogenetics 69, 391–400 (2017).

  99. 99.

    Kapitonov, V. V. & Jurka, J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol. 3, e181 (2005). This study presents the discovery that the RAG1 core is transposed into many vertebrate and invertebrate genomes.

  100. 100.

    Fugmann, S. D., Messier, C., Novack, L. A., Cameron, R. A. & Rast, J. P. An ancient evolutionary origin of the Rag1/2 gene locus. Proc. Natl Acad. Sci. USA 103, 3728–3733 (2006).

  101. 101.

    Kapitonov, V. V. & Koonin, E. V. Evolution of the RAG1-RAG2 locus: both proteins came from the same transposon. Biol. Direct. 10, 20 (2015).

  102. 102.

    Huang, S. et al. Discovery of an active RAG transposon illuminates the origins of V(D)J recombination. Cell 166, 102–114 (2016).

  103. 103.

    Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

  104. 104.

    Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000).

  105. 105.

    Barreto, V. M. & Magor, B. G. Activation-induced cytidine deaminase structure and functions: a species comparative view. Dev. Comp. Immunol. 35, 991–1007 (2011).

  106. 106.

    Saunders, H. L., Oko, A. L., Scott, A. N., Fan, C. W. & Magor, B. G. The cellular context of AID expressing cells in fish lymphoid tissues. Dev. Comp. Immunol. 34, 669–676 (2010).

  107. 107.

    Marr, S. et al. Localization and differential expression of activation-induced cytidine deaminase in the amphibian Xenopus upon antigen stimulation and during early development. J. Immunol. 179, 6783–6789 (2007).

  108. 108.

    Quinlan, E. M., King, J. J., Amemiya, C. T., Hsu, E. & Larijani, M. Biochemical regulatory features of activation-induced cytidine deaminase remain conserved from lampreys to humans. Mol. Cell. Biol. 37, e00077–17 (2017).

  109. 109.

    Barreto, V. M. et al. AID from bony fish catalyzes class switch recombination. J. Exp. Med. 202, 733–738 (2005).

  110. 110.

    Wakae, K. et al. Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID. Int. Immunol. 18, 41–47 (2006).

  111. 111.

    Zhu, C. et al. Origin of immunoglobulin isotype switching. Curr. Biol. 22, 872–880 (2012). This study shows class switch recombination in sharks, despite the cluster-type organization of the IgH genes.

  112. 112.

    Hirano, M. Evolution of vertebrate adaptive immunity: immune cells and tissues, and AID/APOBEC cytidine deaminases. Bioessays 37, 877–887 (2015).

  113. 113.

    Bajoghli, B. et al. A thymus candidate in lampreys. Nature 470, 90–94 (2011). This study presents the completely unanticipated discovery of a thymus-like structure in lampreys, which was christened the thymoid.

  114. 114.

    Nagawa, F. et al. Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nat. Immunol. 8, 206–213 (2007).This study presents a proposal for the assembly of LRR cassettes during gene rearrangement in lamprey lymphocyte development.

  115. 115.

    Nishida, K. et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science 353, aaf8729 (2016).

  116. 116.

    Knisbacher, B. A., Gerber, D. & Levanon, E. Y. DNA editing by APOBECs: a genomic preserver and transformer. Trends Genet. 32, 16–28 (2016).

  117. 117.

    Flajnik, M. F. & Kasahara, M. Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15, 351–362 (2001).

  118. 118.

    Dijkstra, J. M., Grimholt, U., Leong, J., Koop, B. F. & Hashimoto, K. Comprehensive analysis of MHC class II genes in teleost fish genomes reveals dispensability of the peptide-loading DM system in a large part of vertebrates. BMC Evol. Biol. 13, 260 (2013). This study presents the lack of a MHC class II DM gene in fish and discusses MHC class II–peptide assembly prior to the emergence of amphibians.

  119. 119.

    Kaufman, J. F., Flajnik, M. F., Du Pasquier, L. & Riegert, P. Xenopus MHC class II molecules. I. Identification and structural characterization. J. Immunol. 134, 3248–3257 (1985).

  120. 120.

    Criscitiello, M. F. et al. Shark class II invariant chain reveals ancient conserved relationships with cathepsins and MHC class II. Dev. Comp. Immunol. 36, 521–533 (2012).

  121. 121.

    Star, B. & Jentoff, S. Why does the immune system of Atlantic cod lack MHC II? Bioessays 34, 648–651 (2012).

  122. 122.

    Magnadottir, B., Gudmundsdottir, S., Gudmundsdottir, B. K. & Helgason, S. Natural antibodies of cod (Gadus morhua L.): specificity, activity and affinity. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 154, 309–316 (2009).

  123. 123.

    Garrett, T. P., Saper, M. A., Bjorkman, P. J., Strominger, J. L. & Wiley, D. C. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 342, 692–696 (1989).

  124. 124.

    Walker, B. A. et al. The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP)genes. Proc. Natl Acad. Sci. USA 108, 8396–8401 (2011).

  125. 125.

    Flajnik, M. F., Kaufman, J. F., Riegert, P. & Du Pasquier, L. Identification of class I major histocompatibility complex encoded molecules in the amphibian Xenopus. Immunogenetics 20, 433–442 (1984).

  126. 126.

    Flajnik, M. F. et al. A novel type of class I gene organization in vertebrates: a large family of non-MHC-linked class I genes is expressed at the RNA level in the amphibian Xenopus. EMBO J. 12, 4385–4396 (1993). This is the first definitive study on nonclassical MHC class I genes in gnathostomes.

  127. 127.

    Edholm, E. S. et al. Unusual evolutionary conservation and further species-specific adaptations of a large family of nonclassical MHC class Ib genes across different degrees of genome ploidy in the amphibian subfamily Xenopodinae. Immunogenetics 66, 411–426 (2014).

  128. 128.

    Salter-Cid, L., Nonaka, M. & Flajnik, M. F. Expression of MHC class Ia and class Ib during ontogeny: high expression in epithelia and coregulation of class Ia and lmp7 genes. J. Immunol. 160, 2853–2861 (1998).

  129. 129.

    Edholm, E. S. et al. Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians. Proc. Natl Acad. Sci. USA 110, 14342–14347 (2013).This work shows that NKT cells are found in nonmammalian vertebrates, changing the paradigm.

  130. 130.

    Edholm, E. S., Grayfer, L. & Robert, J. Evolution of nonclassical MHC-dependent invariant T cells. Cell. Mol. Life Sci. 71, 4763–4780 (2014).

  131. 131.

    Grimholt, U. et al. A comprehensive analysis of teleost MHC class I sequences. BMC Evol. Biol. 15, 32 (2015).This is an excellent review of teleost MHC class I genes and lineages.

  132. 132.

    Dijkstra, J. M., Yamaguchi, T. & Grimholt, U. Conservation of sequence motifs suggests that the nonclassical MHC class I lineages CD1/PROCR and UT were established before the emergence of tetrapod species. Immunogenetics. (2018).

  133. 133.

    Danchin, E. G. & Pontarotti, P. Towards the reconstruction of the bilaterian ancestral pre-MHC region. Trends Genet. 20, 587–591 (2004).

  134. 134.

    Flajnik, M. F. & Du Pasquier, L. The major histocompatibility complex of frogs. Immunol. Rev. 113, 47–63 (1990).

  135. 135.

    Sato, A. et al. Nonlinkage of major histocompatibility complex class I and class II loci in bony fishes. Immunogenetics 51, 108–116 (2000).

  136. 136.

    Ohta, Y. et al. Primitive synteny of vertebrate major histocompatibility complex class I and class II genes. Proc. Natl Acad. Sci. USA 97, 4712–4717 (2000). This work shows the original linkage of MHC class I and MHC class II genes (in sharks).

  137. 137.

    Ohta, Y. et al. Primordial linkage of β2-microglobulin to the MHC. J. Immunol. 186, 3563–3571 (2011).This work describes the anticipated primordial linkage of β2-microglobulin to the MHC in sharks, which is unlike that found in all other vertebrates.

  138. 138.

    Gruen, J. R. & Weissman, S. M. Human MHC class III and IV genes and disease associations. Front. Biosci. 6, D960–D972 (2001).

  139. 139.

    Salter-Cid, L., Kasahara, M. & Flajnik, M. F. Hsp70 genes are linked to the Xenopus major histocompatibility complex. Immunogenetics 39, 1–7 (1994).

  140. 140.

    Terado, T. et al. Molecular cloning of C4 gene and identification of the class III complement region in the shark MHC. J. Immunol. 171, 2461–2466 (2003).

  141. 141.

    Flajnik, M. F. & Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11, 47–59 (2010).

  142. 142.

    Flajnik, M. F., Tlapakova, T., Criscitiello, M. F., Krylov, V. & Ohta, Y. Evolution of the B7 family: co-evolution of B7H6 and NKp30, identification of a new B7 family member, B7H7, and of B7’s historical relationship with the MHC. Immunogenetics 64, 571–590 (2012).

  143. 143.

    Barten, R., Torkar, M., Haude, A., Trowsdale, J. & Wilson, M. J. Divergent and convergent evolution of NK-cell receptors. Trends Immunol. 22, 52–57 (2001).

  144. 144.

    Rogers, S. L. et al. Characterization of the chicken C-type lectin-like receptors B-NK and B-lec suggests that the NK complex and the MHC share a common ancestral region. J. Immunol. 174, 3475–3483 (2005).This study proposes that the NKC and MHC were syntenic in the proto-MHC.

  145. 145.

    Du Pasquier, L. Several MHC-linked Ig superfamily genes have features of ancestral antigen-specific receptor genes. Curr. Top. Microbiol. Immunol. 266, 57–71 (2002).This study suggests that antigen receptor genes were originally encoded in the primordial MHC.

  146. 146.

    Levasseur, A. & Pontarotti, P. Was the ancestral MHC involved in innate immunity? Eur. J. Immunol. 40, 2682–2685 (2010).

  147. 147.

    Suurvali, J. et al. The proto-MHC of placozoans, a region specialized in cellular stress and ubiquitination/proteasome pathways. J. Immunol. 193, 2891–2901 (2014). This study proposes that the ancestral MHC may have been focused on host recognition elements in the cytosol.

  148. 148.

    Uinuk-Ool, T. et al. Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes. Proc. Natl Acad. Sci. USA 99, 14356–14361 (2002).

  149. 149.

    Suzuki, T., Shin, I., Fujiyama, A., Kohara, Y. & Kasahara, M. Hagfish leukocytes express a paired receptor family with a variable domain resembling those of antigen receptors. J. Immunol. 174, 2885–2891 (2005).

  150. 150.

    Takaba, H. et al. A major allogenic leukocyte antigen in the agnathan hagfish. Sci. Rep. 3, 1716 (2013). References 149 and 150 identify polymorphic IgSF molecules in lamprey, which are potentially involved in antigen presentation.

  151. 151.

    Deng, L. et al. A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey. Proc. Natl Acad. Sci. USA 107, 13408–13413 (2010). This work demonstrates the potential for VLRA (lamprey TCR-equivalent) to bind to free antigen.

  152. 152.

    Uinuk-ool, T. S. et al. Identification and characterization of a TAP-family gene in the lamprey. Immunogenetics 55, 38–48 (2003).

  153. 153.

    Kawai, H. et al. Normal formation of a subset of intestinal granules in Caenorhabditis elegans requires ATP-binding cassette transporters HAF-4 and HAF-9, which are highly homologous to human lysosomal peptide transporter TAP-like. Mol. Biol. Cell 20, 2979–2990 (2009).

  154. 154.

    Bajoghli, B. et al. Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138, 186–197 (2009).

  155. 155.

    Sutoh, Y. et al. Comparative genomic analysis of the proteasome beta5t subunit gene: implications for the origin and evolution of thymoproteasomes. Immunogenetics 64, 49–58 (2012).

  156. 156.

    Saltis, M. et al. Evolutionarily conserved and divergent regions of the autoimmune regulator (Aire) gene: a comparative analysis. Immunogenetics 60, 105–114 (2008).

  157. 157.

    Flajnik, M. Immunology: the origin of sweetbreads in lampreys? Curr. Biol. 21, R218–R220 (2011).

  158. 158.

    Zhang, S. L. & Bhandoola, A. Trafficking to the thymus. Curr. Top. Microbiol. Immunol. 373, 87–111 (2014).

  159. 159.

    Mebius, R. E. & Kraal, G. Structure and function of the spleen. Nat. Rev. Immunol. 5, 606–616 (2005).

  160. 160.

    Neely, H. R. & Flajnik, M. F. CXCL13 responsiveness but not CXCR5 expression by late transitional B cells initiates splenic white pulp formation. J. Immunol. 194, 2616–2623 (2015).

  161. 161.

    Hofmann, J., Greter, M., Du Pasquier, L. & Becher, B. B-cells need a proper house, whereas T-cells are happy in a cave: the dependence of lymphocytes on secondary lymphoid tissues during evolution. Trends Immunol. 31, 144–153 (2010). This is a speculative review on the origins of secondary lymphoid tissues and the segregation of T cell and B cell zones.

  162. 162.

    Lugo-Villarino, G. et al. Identification of dendritic antigen-presenting cells in the zebrafish. Proc. Natl Acad. Sci. USA 107, 15850–15855 (2010).

  163. 163.

    Lewis, K. L., Del, C. N. & Traver, D. Perspectives on antigen presenting cells in zebrafish. Dev. Comp. Immunol. 46, 63–73 (2014).

  164. 164.

    Barreda, D. R., Neely, H. R. & Flajnik, M. F. Evolution of myeloid cells. Microbiol. Spectr. 4, MCHD-0007-2015 (2016).

  165. 165.

    Horton, J. D. & Manning, M. J. Response to skin allografts in Xenopus laevis following thymectomy at early stages of lymphoid organ maturation. Transplantation 14, 141–154 (1972).

  166. 166.

    Baldwin, W. M. III & Cohen, N. A giant cell with dendritic cell properties in spleens of the anuran amphibian Xenopus laevis. Dev. Comp. Immunol. 5, 461–473 (1981).

  167. 167.

    Hsu, E., Flajnik, M. F. & Du Pasquier, L. A third immunoglobulin class in amphibians. J. Immunol. 135, 1998–2004 (1985).

  168. 168.

    Mussmann, R., Du Pasquier, L. & Hsu, E. Is Xenopus IgX an analog of IgA? Eur. J. Immunol. 26, 2823–2830 (1996). This study identifies the mucosal immunoglobulin in amphibians.

  169. 169.

    Mashoof, S. et al. Ancient T-independence of mucosal IgX/A: gut microbiota unaffected by larval thymectomy in Xenopus laevis. Mucosal Immunol. 6, 358–368 (2013).

  170. 170.

    Du, C. C., Mashoof, S. M. & Criscitiello, M. F. Oral immunization of the African clawed frog (Xenopus laevis) upregulates the mucosal immunoglobulin IgX. Vet. Immunol. Immunopathol. 145, 493–498 (2012).

  171. 171.

    Danilova, N., Bussmann, J., Jekosch, K. & Steiner, L. A. The immunoglobulin heavy-chain locus in zebrafish: identification and expression of a previously unknown isotype, immunoglobulin Z. Nat. Immunol. 6, 295–302 (2005).

  172. 172.

    Hansen, J. D., Landis, E. D. & Phillips, R. B. Discovery of a unique Ig heavy-chain isotype (IgT) in rainbow trout: implications for a distinctive B cell developmental pathway in teleost fish. Proc. Natl Acad. Sci. USA 102, 6919–6924 (2005).

  173. 173.

    Zhang, Y. A. et al. IgT, a primitive immunoglobulin class specialized in mucosal immunity. Nat. Immunol. 11, 827–835 (2010). This study identifies the mucosal (and skin)-specific immunoglobulin in bony fish.

  174. 174.

    Rumfelt, L. L., Diaz, M., Lohr, R. L., Mochon, E. & Flajnik, M. F. Unprecedented multiplicity of Ig transmembrane and secretory mRNA forms in the cartilaginous fish. J. Immunol. 173, 1129–1139 (2004).

  175. 175.

    Sepahi, A. & Salinas, I. The evolution of nasal immune systems in vertebrates. Mol. Immunol. 69, 131–138 (2016).

  176. 176.

    Zhu, J. & Paul, W. E. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol. Rev. 238, 247–262 (2010).

  177. 177.

    Dijkstra, J. M. TH2 and Treg candidate genes in elephant shark. Nature 511, E7–E9 (2014). This study proposes that most helper T cell cytokine lineages emerged early in gnathostome evolution.

  178. 178.

    Sugimoto, K., Hui, S. P., Sheng, D. Z., Nakayama, M. & Kikuchi, K. Zebrafish FOXP3 is required for the maintenance of immune tolerance. Dev. Comp. Immunol. 73, 156–162 (2017).

  179. 179.

    Du, P. L. & Bernard, C. C. Active suppression of the allogeneic histocompatibility reactions during the metamorphosis of the clawed toad Xenopus. Differentiation 16, 1–7 (1980).

  180. 180.

    Samstein, R. M., Josefowicz, S. Z., Arvey, A., Treuting, P. M. & Rudensky, A. Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150, 29–38 (2012). This study proposes that pT reg cells emerged in evolution to protect the fetus from anti-paternal immunity.

  181. 181.

    Kang, J. & Malhotra, N. Transcription factor networks directing the development, function, and evolution of innate lymphoid effectors. Annu. Rev. Immunol. 33, 505–538 (2015).

  182. 182.

    Vivier, E., van de Pavert, S. A., Cooper, M. D. & Belz, G. T. The evolution of innate lymphoid cells. Nat. Immunol. 17, 790–794 (2016).

  183. 183.

    Robert, J. & Edholm, E. S. A prominent role for invariant T cells in the amphibian Xenopus laevis tadpoles. Immunogenetics 66, 513–523 (2014).

  184. 184.

    Salomonsen, J. et al. Two CD1 genes map to the chicken MHC, indicating that CD1 genes are ancient and likely to have been present in the primordial MHC. Proc. Natl Acad. Sci. USA 102, 8668–8673 (2005).

  185. 185.

    Miller, M. M. et al. Characterization of two avian MHC-like genes reveals an ancient origin of the CD1 family. Proc. Natl Acad. Sci. USA 102, 8674–8679 (2005).

  186. 186.

    Yang, Z. et al. Analysis of the reptile CD1 genes: evolutionary implications. Immunogenetics 67, 337–346 (2015).

  187. 187.

    Edholm, E. S., Banach, M. & Robert, J. Evolution of innate-like T cells and their selection by MHC class I-like molecules. Immunogenetics 68, 525–536 (2016).

  188. 188.

    Valiante, N. M., Lienert, K., Shilling, H. G., Smits, B. J. & Parham, P. Killer cell receptors: keeping pace with MHC class I evolution. Immunol. Rev. 155, 155–164 (1997).

  189. 189.

    Wcisel, D. J. & Yoder, J. A. The confounding complexity of innate immune receptors within and between teleost species. Fish Shellfish Immunol. 53, 24–34 (2016).

  190. 190.

    Shen, L. et al. Channel catfish NK-like cells are armed with IgM via a putative FcmicroR. Dev. Comp. Immunol. 27, 699–714 (2003).

  191. 191.

    Shen, L. et al. Channel catfish cytotoxic cells: a mini-review. Dev. Comp. Immunol. 26, 141–149 (2002).

  192. 192.

    Horton, T. L. et al. Ontogeny of Xenopus NK cells in the absence of MHC class I antigens. Dev. Comp. Immunol. 27, 715–726 (2003).

  193. 193.

    Brandt, C. S. et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J. Exp. Med. 206, 1495–1503 (2009).

  194. 194.

    Kasheta, M. et al. Identification and characterization of T reg-like cells in zebrafish. J. Exp. Med. 214, 3519–3530 (2017).

  195. 195.

    Hui, S. P. et al. Zebrafish regulatory T cells mediate organ-specific regenerative programs. Dev. Cell 43, 659–672.e5 (2017).

  196. 196.

    Eason, D. D., Litman, R. T., Luer, C. A., Kerr, W. & Litman, G. W. Expression of individual immunoglobulin genes occurs in an unusual system consisting of multiple independent loci. Eur. J. Immunol. 34, 2551–2558 (2004).

  197. 197.

    Malecek, K. et al. Immunoglobulin heavy chain exclusion in the shark. PLoS Biol. 6, e157 (2008). References 196 and 197 show that, despite the cluster-type organization of cartilaginous fish immunoglobulin genes, there is clonal expression of B cell receptors.

  198. 198.

    Greenberg, A. S. et al. A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks. Nature 374, 168–173 (1995). This study presents the discovery of a single-domain immunoglobulin in sharks.

  199. 199.

    Kokubu, F., Hinds, K., Litman, R., Shamblott, M. J. & Litman, G. W. Complete structure and organization of immunoglobulin heavy chain constant region genes in a phylogenetically primitive vertebrate. EMBO J. 7, 1979–1988 (1988). Discovery of RAG activity in germ cells, resulting in germline-joined Ig genes in cartilaginous fish.

  200. 200.

    Lee, S. S., Fitch, D., Flajnik, M. F. & Hsu, E. Rearrangement of immunoglobulin genes in shark germ cells. J. Exp. Med. 191, 1637–1648 (2000).

  201. 201.

    Rumfelt, L. L. et al. A shark antibody heavy chain encoded by a nonsomatically rearranged VDJ is preferentially expressed in early development and is convergent with mammalian IgG. Proc. Natl Acad. Sci. USA 98, 1775–1780 (2001).

  202. 202.

    Rollins-Smith, L. A. Metamorphosis and the amphibian immune system. Immunol. Rev. 166, 221–230 (1998).

  203. 203.

    Lee, A. & Hsu, E. Isolation and characterization of the Xenopus terminal deoxynucleotidyl transferase. J. Immunol. 152, 4500–4507 (1994).

  204. 204.

    Flajnik, M. F. et al. Major histocompatibility complex-encoded class I molecules are absent in immunologically competent Xenopus before metamorphosis. J. Immunol. 137, 3891–3899 (1986).

  205. 205.

    Ota, T. et al. Positive Darwinian selection operating on the immunoglobulin heavy chain of Antarctic fishes. J. Exp. Zool. B Mol. Dev. Evol. 295, 45–58 (2003).

  206. 206.

    Pucci, B., Coscia, M. R. & Oreste, U. Characterization of serum immunoglobulin M of the Antarctic teleost Trematomus bernacchii. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 135, 349–357 (2003).

  207. 207.

    Coscia, M. R., Varriale, S., Giacomelli, S. & Oreste, U. Antarctic teleost immunoglobulins: more extreme, more interesting. Fish Shellfish Immunol. 31, 688–696 (2011). References 205–207 detail fascinating modifications to the immunoglobulins of cold-water bony fish.

  208. 208.

    Flajnik, M. F., Ohta, Y., Namikawa-Yamada, C. & Nonaka, M. Insight into the primordial MHC from studies in ectothermic vertebrates. Immunol. Rev. 167, 59–67 (1999).

  209. 209.

    Kaufman, J. Co evolving genes in MHC haplotypes: the “rule” for nonmammalian vertebrates? Immunogenetics 50, 228–236 (1999).

  210. 210.

    Heink, S., Ludwig, D., Kloetzel, P. M. & Kruger, E. IFN-gamma-induced immune adaptation of the proteasome system is an accelerated and transient response. Proc. Natl Acad. Sci. USA 102, 9241–9246 (2005).

  211. 211.

    Parra, Z. E. et al. A unique T cell receptor discovered in marsupials. Proc. Natl Acad. Sci. USA 104, 9776–9781 (2007).

  212. 212.

    Schild, H. et al. The nature of major histocompatibility complex recognition by gamma delta T cells. Cell 76, 29–37 (1994). This study presents the original proposal that γδ T cells recognize free antigen.

  213. 213.

    Li, J. et al. B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities. Nat. Immunol. 7, 1116–1124 (2006). This work shows that B cells from bony fish and other ectothermic vertebrates are capable of phagocytosis.

  214. 214.

    Parra, D. et al. Pivotal advance: peritoneal cavity B-1 B cells have phagocytic and microbicidal capacities and present phagocytosed antigen to CD4 + T cells. J. Leukoc. Biol. 91, 525–536 (2012).

  215. 215.

    Fites, J. S. et al. The invasive chytrid fungus of amphibians paralyzes lymphocyte responses. Science 342, 366–369 (2013).

  216. 216.

    Holden, W. M., Reinert, L. K., Hanlon, S. M., Parris, M. J. & Rollins-Smith, L. A. Development of antimicrobial peptide defenses of southern leopard frogs. Rana sphenocephala, against the pathogenic chytrid fungus, Batrachochytrium dendrobatidis. Dev. Comp. Immunol. 48, 65–75 (2015).

  217. 217.

    Kosch, T. A. et al. Major histocompatibility complex selection dynamics in pathogen-infected tungara frog (Physalaemus pustulosus) populations. Biol. Lett. 12, 20160345 (2016).

  218. 218.

    Bataille, A. et al. Susceptibility of amphibians to chytridiomycosis is associated with MHC class II conformation. Proc. Biol. Sci. 282, 20143127 (2015).

  219. 219.

    Lien, S. et al. The Atlantic salmon genome provides insights into rediploidization. Nature 533, 200–205 (2016).

  220. 220.

    Session, A. M. et al. Genome evolution in the allotetraploid frog Xenopus laevis. Nature 538, 336–343 (2016).

  221. 221.

    Kobel, H. R. & Du Pasquier, L. Genetics of polyploid Xenopus. Trends Genet. 12, 310–314 (1986).

  222. 222.

    Zwollo, P. Why spawning salmon return to their natal stream: the immunological imprinting hypothesis. Dev. Comp. Immunol. 38, 27–29 (2012).

  223. 223.

    Chappell, M. E., Epp, L. & Zwollo, P. Sockeye salmon immunoglobulin VH usage and pathogen loads differ between spawning sites. Dev. Comp. Immunol. 77, 297–306 (2017).

  224. 224.

    Makela, O. & Litman, G. W. Lack of heterogeneity in antihapten antibodies of a phylogenetically primitive shark. Nature 287, 639–640 (1980).

  225. 225.

    Hinds-Frey, K. R., Nishikata, H., Litman, R. T. & Litman, G. W. Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity. J. Exp. Med. 178, 815–824 (1993). This is the first description of somatic hypermutation of IgV genes in ectothermic vertebrates.

  226. 226.

    Krautler, N. J. et al. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell 150, 194–206 (2012).

  227. 227.

    Kasahara, M. et al. Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex. Proc. Natl Acad. Sci. USA 93, 9096–9101 (1996). This is the first study to demonstrate MHC paralogous regions, consistent with Ohno’s proposal of two genome-wide duplications early in vertebrate history.

  228. 228.

    Abi-Rached, L., Gilles, A., Shiina, T., Pontarotti, P. & Inoko, H. Evidence of en bloc duplication in vertebrate genomes. Nat. Genet. 31, 100–105 (2002). This paper provides our working model of the proto-MHC in a lower deuterostome, amphioxus.

Download references


The authors thank L. Du Pasquier and H. Matz for critical reading. M.F.F. has been supported by US National Institutes of Health (NIH) grants R01OD049 and RO1AI027877.

Author information


  1. Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD, USA

    • Martin F. Flajnik


  1. Search for Martin F. Flajnik in:


M.F.F. was responsible for the reading, writing and revising this manuscript.

Competing interests

The author declares no competing interests.

Corresponding author

Correspondence to Martin F. Flajnik.


Bursa of Fabricius

An organ derived from a cloacal outpocketing in birds in which B cells develop.


Embryonically, animals in which the blastopore becomes the anus, including all of the vertebrates. Lower deuterostomes such as tunicates, lancelets and echinoderms are descendants of ancestors before the emergence of adaptive immunity and the genome-wide duplications that occurred early in vertebrate history.


Jawed vertebrates, including placoderms, cartilaginous fish, bony fish, amphibians, reptiles, birds and mammals.

Evolutionary ‘Big Bang’

The rapid emergence of the majority of molecules, mechanisms and tissues that define human adaptive immunity, which most likely occurred in placoderms (see Fig. 2).

Variable lymphocyte receptors

(VLRs). Antigen receptors (VLRA and VLRB) found in the agnathan jawless fish (lamprey and hagfish).

Follicular dendritic cells

(FDCs). Cells found in only warm-blooded vertebrates that present native antigen to B cells in the follicles and germinal centres of secondary lymphoid organs.

Immunoglobulin superfamily

A family containing proteins with a specific immunoglobulin superfamily (IgSF) domain, including molecules such as immunoglobulins, T cell receptors and MHC class I and MHC class II molecules, in which there are unique members of the superfamily (VJ and C1 domains).


The most ancient extant vertebrates (lamprey and hagfish), which lack jaws.


A genus of aquatic amphibians that is a widespread model for basic science research, including in comparative immunology.


Vertebrates that serve as a tractable model for the transition from fish to tetrapods and share features with both groups.


Vertebrates with lobed fins, once thought to be extinct, that serve as a model for the transition from fish to tetrapods.

‘Dead end’ H chain immunoglobulin isotypes

Immunoglobulin heavy (H) chain isotypes that arose in particular vertebrate taxa but are apparently not perpetuated throughout the vertebrate tree.

Somatic hypermutation

(SHM). A process that introduces activation-induced cytidine deaminase (AID)-initiating mutations into the immunoglobulin variable region genes of B cells during an adaptive immune response.

Complementarity determining regions

(CDRs). Loops on one face of variable immunoglobulin superfamily domains in regions of both immunoglobulins and T cell receptors that contact antigen (or antigenic peptide–MHC complexes) and that display the greatest variability.


A complementarity determining region (CDR) that is generally considered to be the most diverse part of the immunoglobulin and T cell receptor binding site and is derived from recombination-activating gene (RAG)-mediated rearrangements during lymphocyte ontogeny.

RAG transposon

A hypothetical transposable element that contains insertion elements, recombination signal sequences and (at least) one gene encoding the V(D)J recombination-activating protein 1 (RAG1) catalytic core, which invaded an immunoglobulin superfamily gene, initiating the generation of diversity in antigen receptor genes.

Switch boxes

Repetitive DNA elements upstream of every immunoglobulin H (IgH) isotype gene in mammals that are involved in class switch recombination.

APOBEC family

A specialized family of cytidine deaminases (CDAs) of which the best studied is activation-induced cytidine deaminase (AID), including its function in somatic hypermutation and class switch recombination. Members found in jawless fish (CDA1 and CDA2) are implicated in the rearrangement of the variable lymphocyte receptor genes, and other APOBEC family members in mammals are involved in viral defence and genome preservation.

Copy choice

The gene conversion-like mechanism by which diversity is generated for the variable lymphocyte receptor genes in developing agnathan T and B cells.


The evolutionarily oldest nonclassical (MHC class Ib) molecule that presents lipid antigens to natural killer T cells and a subset of γδ T cells.

NK gene complex

(NKC). A large family of C-type lectin genes in mammals involved primarily in natural killer (NK) cell recognition (for example, killer cell lectin-like receptor subfamily K member 1 (KLRK1) and CD94).

Leukocyte immunoglobulin-like receptor complex

(LRC). A large family of immunoglobulin superfamily genes in mammals (found on chromosome 19 in humans) involved in many immune reactions, including natural killer cell receptors.

Proteasome subunit-β type 11

(PSMβ11). Also known as B5T; an immunoproteasome catalytic subunit expressed specifically by the thymic cortical epithelium in all gnathostomes that is vital for the production of peptides involved in the positive selection of CD8+ T cells (cytotoxic T cells).

Autoimmune regulator

(AIRE). A protein that is expressed specifically by the thymic medullary epithelium in all gnathostomes and is vital for central tolerance of T cells via the expression of tissue-specific antigens.

Peanut agglutinin staining

A process that makes use of lectin, which recognizes de-sialylated glycoproteins, most conspicuously staining germinal centre B cells, double-positive thymocytes and dendritic cell subsets.

About this article

Publication history



Further reading