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The origins of vertebrate adaptive immunity

Nature Reviews Immunology volume 10, pages 543–553 (2010)Cite this article

Subjects

Key Points

  • Innate immunity has a long phylogenetic history, encompassing species as diverse as sea anemones, insects and mammals. By contrast, adaptive immunity, which involves lymphocyte-like cells and the antigen-binding receptors they express, is restricted to vertebrates.

  • A major departure in adaptive immunity is evident within vertebrate species. Jawed vertebrates use V(D)J recombination of immunoglobulin and T cell receptors, whereas jawless vertebrates rearrange variable lymphocyte receptors encoding leucine-rich repeats to form an alternative type of immune receptor.

  • Homologues of molecules that previously were thought to be unique to the rearrangement and diversification of immunoglobulin and T cell receptors have been identified in invertebrate species, in which these forms of immune recognition molecules are absent.

  • The enormously complex, multifactorial and highly regulated cellular processes that generate receptor variation in somatic cells arose through the integration of molecular systems that are not exclusively associated with immune diversity.

  • Reconstructing the nature of ancestral forms of adaptive immune receptors is compromised by the absence of crucial intermediates; however, it is possible to infer some of the main steps that gave rise to the antigen receptor-bearing immunocytes of jawed vertebrates.

Abstract

Adaptive immunity is mediated through numerous genetic and cellular processes that generate favourable somatic variants of antigen-binding receptors under evolutionary selection pressure by pathogens and other factors. Advances in our understanding of immunity in mammals and other model organisms are revealing the underlying basis and complexity of this remarkable system. Although the evolution of adaptive immunity has been thought to occur by the acquisition of novel molecular capabilities, an increasing amount of information from new model systems suggest that co-option and redirection of pre-existing systems are the main source of innovation. We combine evidence from a wide range of organisms to obtain an integrated view of the origins and patterns of divergence in adaptive immunity.

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Figure 1: Lymphocyte development and antigen receptor diversification in jawed vertebrates.
Figure 2: Relationships among animal phyla and subphyla with direct bearing on the origins of V(D)J recombination in jawed vertebrates.
Figure 3: Evolutionary co-option of ancient biological systems into lymphocytes that express V(D)J receptors.

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References

  1. Litman, G. W., Cannon, J. P. & Dishaw, L. J. Reconstructing immune phylogeny: new perspectives. Nature Rev. Immunol. 5, 866–879 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Gellert, M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu. Rev. Biochem. 71, 101–132 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Flajnik, M. F. Comparative analyses of immunoglobulin genes: surprises and portents. Nature Rev. Immunol. 2, 688–698 (2002).

    Article  CAS  Google Scholar 

  7. Kokubu, F., Litman, R., Shamblott, M. J., Hinds, K. & Litman, G. W. Diverse organization of immunoglobulin VH gene loci in a primitive vertebrate. EMBO J. 7, 3413–3422 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Richards, M. H. & Nelson, J. L. The evolution of vertebrate antigen receptors: a phylogenetic approach. Mol. Biol. Evol. 17, 146–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Rast, J. P. et al. α, β, γ, and δ T cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 6, 1–11 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Miracle, A. L. et al. Complex expression patterns of lymphocyte-specific genes during the development of cartilaginous fish implicate unique lymphoid tissues in generating an immune repertoire. Int. Immunol. 13, 567–580 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Pollara, B., Litman, G. W., Finstad, J., Howell, J. & Good, R. A. The evolution of the immune response. VII. Antibody to human “O” cells and properties of the immunoglobulin in lamprey. J. Immunol. 105, 738–745 (1970).

    CAS  PubMed  Google Scholar 

  17. Litman, G. W., Anderson, M. K. & Rast, J. P. Evolution of antigen binding receptors. Ann. Rev. Immunol. 17, 109–147 (1999).

    Article  CAS  Google Scholar 

  18. Alder, M. N. et al. Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310, 1970–1973 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Saha, N. R., Smith, J. & Amemiya, C. T. Evolution of adaptive immune recognition in jawless vertebrates. Semin. Immunol. 22, 25–33 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mayer, W. E. et al. Isolation and characterization of lymphocyte-like cells from a lamprey. Proc. Natl Acad. Sci. USA 99, 14350–14355 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Pancer, Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004). An important paper that reports the existence of a new diversified antigen receptor that is the basis for adaptive immunity in jawless vertebrates.

    Article  CAS  PubMed  Google Scholar 

  25. Pancer, Z. et al. Variable lymphocyte receptors in hagfish. Proc. Natl Acad. Sci. USA 102, 9224–9229 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Han, B. W., Herrin, B. R., Cooper, M. D. & Wilson, I. A. Antigen recognition by variable lymphocyte receptors. Science 321, 1834–1837 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Velikovsky, C. A. et al. Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen. Nature Struct. Mol. Biol. 16, 725–730 (2009).

    Article  CAS  Google Scholar 

  28. Smith, J. J., Antonacci, F., Eichler, E. E. & Amemiya, C. T. Programmed loss of millions of base pairs from a vertebrate genome. Proc. Natl Acad. Sci. USA 106, 11212–11217 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nagawa, F. et al. Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nature Immunol. 8, 206–213 (2007). The authors provide the first experimental data in support of a copy choice model for the assembly of VLR genes in jawless vertebrates.

    Article  CAS  Google Scholar 

  30. Rogozin, I. B. et al. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID–APOBEC family cytosine deaminase. Nature Immunol. 8, 647–656 (2007). The authors identify two cytidine deaminases with homology to AID and, based on the expression pattern, suggest that these enzymes are involved in the diversification of the VLR repertoire in lampreys.

    Article  CAS  Google Scholar 

  31. Kishishita, N. et al. Regulation of antigen-receptor gene assembly in hagfish. EMBO Rep. 11, 126–132 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tasumi, S. et al. High-affinity lamprey VLRA and VLRB monoclonal antibodies. Proc. Natl Acad. Sci. USA 106, 12891–12896 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thompson, C. B. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3, 531–539 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Marchalonis, J. J., Schluter, S. F., Bernstein, R. M. & Hohman, V. S. Antibodies of sharks: revolution and evolution. Immunol. Rev. 166, 103–122 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Holland, L. Z. et al. The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res. 18, 1100–1111 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hibino, T. et al. The immune gene repertoire encoded in the purple sea urchin genome. Dev. Biol. 300, 349–365 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Azumi, K. et al. Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: “waiting for Godot”. Immunogenetics 55, 570–581 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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). This is the first report of a RAG1 - and RAG2 -like gene cluster outside the jawed vertebrate lineage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 report identifies the striking similarity between RAG1 and Transib transposons, a widespread family of mobile DNA elements.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Fugmann, S. D. The origins of the Rag genes — from transposition to V(D)J recombination. Semin. Immunol. 22, 10–16 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Matthews, A. G. et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450, 1106–1110 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu, Y., Subrahmanyam, R., Chakraborty, T., Sen, R. & Desiderio, S. A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27, 561–571 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wilson, D. R., Norton, D. D. & Fugmann, S. D. The PHD domain of the sea urchin RAG2 homolog, SpRAG2L, recognizes dimethylated lysine 4 in histone H3 tails. Dev. Comp. Immunol. 32, 1221–1230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ji, Y. et al. The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell 141, 419–431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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, 825–834 (1993).

    Article  Google Scholar 

  47. Diaz, M., Greenberg, A. S. & Flajnik, M. F. Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: possible role in antigen-driven reactions in the absence of germinal centers. Proc. Natl Acad. Sci. USA 95, 14343–14348 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. Hayakawa, K. & Hardy, R. R. Development and function of B-1 cells. Curr. Opin. Immunol. 12, 346–353 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Takagaki, Y., Seipelt, R. L., Peterson, M. L. & Manley, J. L. The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell 87, 941–952 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Martincic, K., Alkan, S. A., Cheatle, A., Borghesi, L. & Milcarek, C. Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing. Nature Immunol. 10, 1102–1109 (2009).

    Article  CAS  Google Scholar 

  52. Sciammas, R. & Davis, M. M. Blimp-1; immunoglobulin secretion and the switch to plasma cells. Curr. Top. Microbiol. Immunol. 290, 201–224 (2005).

    CAS  PubMed  Google Scholar 

  53. Sciammas, R. & Davis, M. M. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. J. Immunol. 172, 5427–5440 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Heaney, M. L. & Golde, D. W. Soluble receptors in human disease. J. Leukoc. Biol. 64, 135–146 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Butler, J. E. Immunoglobulin diversity, B-cell and antibody repertoire development in large farm animals. Rev. Sci. Tech. 17, 43–70 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Longerich, S., Basu, U., Alt, F. & Storb, U. AID in somatic hypermutation and class switch recombination. Curr. Opin. Immunol. 18, 164–174 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Di Noia, J. M. & Neuberger, M. S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. Malecek, K. et al. Immunoglobulin heavy chain exclusion in the shark. PLoS Biol. 6, e157 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Harris, R. S. & Liddament, M. T. Retroviral restriction by APOBEC proteins. Nature Rev. Immunol. 4, 868–877 (2004).

    Article  CAS  Google Scholar 

  61. Zarrin, A. A. et al. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nature Immunol. 5, 1275–1281 (2004).

    Article  CAS  Google Scholar 

  62. Weinstein, J. A., Jiang, N., White, R. A., Fisher, D. S. & Quake, S. R. Sequencing the zebrafish immune repertoire. Science 324, 807–810 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, H. et al. Characterization of arrangement and expression of the T cell receptor γ locus in the sandbar shark. Proc. Natl Acad. Sci. USA 106, 8591–8596 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. O'Brien, R. L. & Born, W. K. γδ T cell subsets: A link between TCR and function? Semin. Immunol. 5 May 2010 (doi:10.1016/j.smim.2010.03.006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Van Rhijn, I. et al. Highly diverse TCR δ chain repertoire in bovine tissues due to the use of up to four D segments per δ chain. Mol. Immunol. 44, 3155–3161 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Boehm, T. Co-evolution of a primordial peptide-presentation system and cellular immunity. Nature Rev. Immunol. 6, 79–84 (2006).

    Article  CAS  Google Scholar 

  67. Boehm, T. & Bleul, C. C. The evolutionary history of lymphoid organs. Nature Immunol. 8, 131–135 (2007).

    Article  CAS  Google Scholar 

  68. Li, J. et al. B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities. Nature Immunol. 7, 1116–1124 (2006).

    Article  CAS  Google Scholar 

  69. Guo, P. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009). This work reports that VLR-expressing lymphocyte-like cells can be divided into two classes that are reminiscent of the humoral (B cells) and cellular (T cells) arms of the conventional adaptive immune system in jawed vertebrates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dermody, T. S., Kirchner, E., Guglielmi, K. M. & Stehle, T. Immunoglobulin superfamily virus receptors and the evolution of adaptive immunity. PLoS Pathog. 5, e1000481 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Yoder, J. A. et al. Resolution of the NITR gene cluster in zebrafish. Proc. Natl Acad. Sci. USA 101, 15706–15711 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cannon, J. P. et al. A bony fish immunological receptor of the NITR multigene family mediates allogeneic recognition. Immunity 29, 228–237 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cannon, J. P., Haire, R. N. & Litman, G. W. Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate. Nature Immunol. 3, 1200–1207 (2002). This article describes the identification of a highly diverse family of immunoglobulin receptors in amphioxus and raises the possibility that invertebrates may also rely on diversified antigen receptors for immunity, a characteristic previously thought to be exclusive to jawed vertebrates.

    Article  CAS  Google Scholar 

  74. Cannon, J. P., Haire, R. N., Schnitker, N., Mueller, M. G. & Litman, G. W. Individual protochordates possess unique immune-type receptor repertoires. Curr. Biol. 14, R465–R466 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Hernandez Prada, J. A. et al. Ancient evolutionary origin of diversified variable regions revealed by crystal structures of an immune-type receptor in amphioxus. Nature Immunol. 7, 875–882 (2006).

    Article  CAS  Google Scholar 

  76. Dishaw, L. J. et al. Genomic complexity of the variable region-containing chitin-binding proteins in amphioxus. BMC Genetics 9, 78 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Miller, R. D. Those other mammals: the immunoglobulins and T cell receptors of marsupials and monotremes. Semin. Immunol. 22, 3–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Rothenberg, E. V. & Pant, R. Origins of lymphocyte developmental programs: transcription factor evidence. Semin. Immunol. 16, 227–238 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Anderson, S. K. Transcriptional regulation of NK cell receptors. Curr. Top. Microbiol. Immunol. 298, 59–75 (2006).

    CAS  PubMed  Google Scholar 

  82. Rast, J. P., Smith, L. C., Loza-Coll, M., Hibino, T. & Litman, G. W. Genomic insights into the immune system of the sea urchin. Science 314, 952–956 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pancer, Z. & Cooper, M. D. The evolution of adaptive immunity. Ann. Rev. Immunol. 24, 497–518 (2006).

    Article  CAS  Google Scholar 

  84. Zhang, Q. et al. Novel genes dramatically alter regulatory network topology in amphioxus. Genome Biol. 9, R123 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Huang, S. et al. Genomic analysis of the immune gene repertoire of amphioxus reveals extraordinary innate complexity and diversity. Genome Res. 18, 1112–1126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Davidson, C. R., Best, N. M., Francis, J. W., Cooper, E. L. & Wood, T. C. Toll-like receptor genes (TLRs) from Capitella capitata and Helobdella robusta (Annelida). Dev. Comp. Immunol. 32, 608–612 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Messier-Solek, C., Buckley, K. M. & Rast, J. P. Highly diversified innate receptor systems and new forms of animal immunity. Semin. Immunol. 22, 39–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Flajnik, M. F. & Du, P. L. Evolution of innate and adaptive immunity: can we draw a line? Trends Immunol. 25, 640–644 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Lieber, M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181–211 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Weller, G. R. et al. Identification of a DNA nonhomologous end-joining complex in bacteria. Science 297, 1686–1689 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Meek, K., Gupta, S., Ramsden, D. A. & Lees-Miller, S. P. The DNA-dependent protein kinase: the director at the end. Immunol. Rev. 200, 132–141 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Gozalbo-Lopez, B. et al. A role for DNA polymerase μ in the emerging DJH rearrangements of the postgastrulation mouse embryo. Mol. Cell Biol. 29, 1266–1275 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Davidson, E. H. & Erwin, D. H. Gene regulatory networks and the evolution of animal body plans. Science 311, 796–800 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work in the laboratory of G.W.L. is supported by US National Institutes of Health grants AI23338 and AI57559. The work in the laboratory of J.P.R. is supported by Canadian Institutes for Health Research grant MOP74667 and National Science and Engineering Research Council of Canada grant NSERC 458115/211598. The work in the laboratory of S.D.F. is supported by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging.

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Authors and Affiliations

  1. Department of Molecular Genetics, All Children's Hospital, St. Petersburg, 33701, Florida, USA

    Gary W. Litman

  2. Department of Pediatrics, University of South Florida College of Medicine, St Petersburg, 33701, Florida, USA

    Gary W. Litman

  3. H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, Florida, USA

    Gary W. Litman

  4. Department of Medical Biophysics and Department of Immunology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, M4N 3M5, Ontario, Canada

    Jonathan P. Rast

  5. Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, 21224, Maryland, USA

    Sebastian D. Fugmann

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Glossary

Somatic hypermutation

(SHM). The process by which point mutations are introduced in the heavy- or light-chain variable region gene segments, resulting in a change in the expressed protein, which may alter affinity or specificity for antigen.

V(D)J recombination

The lineage-specific RAG1- and RAG2-mediated assembly of functional immunoglobulin and T cell receptor genes from individual variable (V), diversity (D) and joining (J) gene segments. This process occurs exclusively in B and T cell progenitors.

Recombination signal sequences

(RSSs). Highly conserved heptamer and nonomer sequences that flank recombining segmental elements in immunoglobulin and T cell receptor genes. These sequences are separated by 12 or 23 base pair spacers that are required to direct the recombination of compatible elements.

Recombination-activating gene 1

(RAG1). A protein that, along with RAG2, forms a DNA recombinase complex which catalyses V(D)J recombination. During the joining phase additional ubiquitous DNA repair factors are recruited. Both genes are exclusively expressed in developing lymphocytes.

Gene conversion

An immunoglobulin gene diversification process closely related to somatic hypermutation. In general, U:G base mismatches are repaired by copying sequence information from upstream pseudo V segments into the rearranged VJ and VDJ exon of the IgL and IgH genes, respectively. In birds and rabbits it occurs before antigen encounter.

Tetrapods

Four-limbed vertebrates that include the amphibians and amniotes (reptiles, birds and mammals). These groups share some common immune features, such as class-switch recombination.

Activation-induced cytidine deaminase

(AID). An enzyme that acts on single-stranded DNA and converts cytidines to uracils. It is typically expressed in B cells after antigen encounter. Its mutagenic activity is restricted to immunoglobulin loci.

Phylogeny

The study of evolutionary relatedness among groups or species of organisms. Similar analyses can be applied to relatedness among genes.

Lampreys and hagfish

Two extant groups of the jawless vertebrate lineage that have anatomical and physiological differences from jawed vertebrates. Lampreys undergo metamorphosis from a larval form, termed an ammocoete, and approximately half of the species are parasitic in adult life. Hagfish are ocean dwelling species that feed on decaying animal matter and small crustaceans.

Leucine-rich repeat

(LRR). A protein structural motif that is comprised of 20–30 amino acid regions that are unusually rich in the hydrophobic amino acid leucine and form a characteristic structural fold.

Copy choice mechanism of recombination

A genetic recombination mechanism in which a new DNA sequence is generated by replication using multiple DNA sequences as templates. The DNA polymerase continues to synthesize a single DNA molecule while jumping from one template strand to another. The choice of templates is largely driven by sequence homologies, allowing the previously synthesized DNA to anneal to similar sequences elsewhere in the genome and thereby redirecting DNA synthesis.

Chordates

An animal phylum that comprises both jawed and jawless vertebrates, and two subphyla of invertebrates: the cephalochordates (such as amphioxus) and the urochordates (such as the sea squirt Ciona intestinalis).

Deuterostomes

An animal superphylum composed of four phyla: the chordates (which include vertebrates), the echinoderms (consisting of starfish, sea urchins and allied species), the hemichordates (acorn worms) and Xenoturbellida (containing two marine worm-like species). Genomes from each of the three main deuterostome phyla have been sequenced.

Transposons

(Also are known as 'jumping genes' and 'selfish DNA'). DNA sequences that encode transposases, the enzymes required to excise the transposon from its original chromosomal location and to integrate it in a different position within the genome. The ends of transposons consist of DNA repeats that serve as recognition sites for the transposase itself.

Purple sea urchin

(Strongylocentrotus purpuratus). An echinoderm that is a well established model system for developmental biology. Sequencing of its genome increased the interest of the broader scientific community (including immunologists) in this invertebrate model system.

Complementarity determining region 3

(CDR3). The region in B and T cell receptors that interacts with the antigen, in which hypervariable sequences are located. CDR3 typically is derived somatically, whereas CDR1 and CDR2 are germline encoded.

B-1 B cells

In mice, this B cell subset is found mainly in the peritoneal and pleural cavities. B-1 B cells are a self-renewing subset with a restricted repertoire of B cell receptors that respond to common bacterial antigens and have a role in autoimmunity.

Derived evolutionary features

Anatomical structures, genes or functional systems are designated as derived when they originate within a sub-lineage. Primitive evolutionary features refer to those that originate from similar features in a common ancestor.

Invariant natural killer T (iNKT) cells

Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα gene segment to yield T cell receptor α-chains with an invariant sequence.

Novel immune-type receptors

(NITRs). Activating or inhibitory receptors that are encoded by large diversified multigene families in bony fish. All NITRs have a variable region and most have a transmembrane region and cytoplasmic tail with signalling motifs.

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Litman, G., Rast, J. & Fugmann, S. The origins of vertebrate adaptive immunity. Nat Rev Immunol 10, 543–553 (2010). https://doi.org/10.1038/nri2807

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