Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Design principles of adaptive immune systems

Key Points

  • Both jawless vertebrates, such as lampreys and hagfish, and jawed vertebrates (encompassing species as diverse as sharks and humans) possess T-like and B-like lymphocytes.

  • Jawless vertebrates use variable lymphocyte receptors (VLRs) consisting of leucine-rich repeats whereas jawed vertebrates rely on antigen receptors of the immunoglobulin superfamily, such as immunoglobulins and T cell receptors (TCRs).

  • All vertebrates use somatic diversification to generate highly diverse repertoires of antigen receptors. Jawless vertebrates diversify their VLR genes by a process akin to gene conversion, whereas the diversification of immunoglobulin and TCR genes is achieved by the process of V(D)J recombination.

  • T-like cells develop in the thymoids of lampreys and the thymus of jawed vertebrates, whereas B cells develop in anatomically distinct haematopoietic tissues.

  • The astounding sequence diversity of the VLRA receptors expressed by T-like cells of lampreys suggests that mechanisms exist to tame potential self-reactivity; the search for an MHC equivalent is one of the priorities in the study of cellular immunity in jawless vertebrates.

Abstract

Both jawless vertebrates, such as lampreys and hagfish, and jawed vertebrates (encompassing species as diverse as sharks and humans) have an adaptive immune system that is based on somatically diversified and clonally expressed antigen receptors. Although the molecular nature of the antigen receptors and the mechanisms of their assembly are different, recent findings suggest that the general design principles underlying the two adaptive immune systems are surprisingly similar. The identification of such commonalities promises to further our understanding of the mammalian immune system and to inspire the development of new strategies for medical interventions targeting the consequences of faulty immune functions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Evolutionary origin of lymphocytes.
Figure 2: Structure of antigen receptor genes.
Figure 3: Distribution of thymopoietic tissues in the gill basket of lamprey larvae.
Figure 4: The evolutionary emergence of thymopoiesis.
Figure 5: Spatially separated development and functional interaction of vertebrate lymphocytes.

Similar content being viewed by others

References

  1. Heimberg, A. M., Cowper-Sal-lari, R., Sémon, M., Donoghue, P. C. J. & Peterson, K. J. microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate. Proc. Natl Acad. Sci. USA 107, 19379–19383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Janvier, P. Early jawless vertebrates and cyclostome origins. Zool. Sci. 25, 1045–1056 (2008).

    Article  Google Scholar 

  3. Schaffer, J. Ueber die Thymusanlage bei Petromyzon Planeri. Zweite vorläufige Mittheilung über den feineren Bau des Thymus. Sitzungsberichte der K. Akad. der Wissenschaften Math. Nat. Klasse Abth. III 103, 149–156 (1894).

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Guo, P. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009). This study identified two distinct lymphocyte lineages in lamprey larvae, indicating that the functional dichotomy of B and T cells is common to all vertebrates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pancer, Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004). This paper describes a novel somatic diversification system for antigen receptors in lampreys.

    CAS  PubMed  Google Scholar 

  8. Cooper, M. D. & Alder, M. N. The evolution of adaptive immune systems. Cell 124, 815–822 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Cooper, M. D. & Herrin, B. R. How did our complex immune system evolve? Nature Rev. Immunol. 10, 2–3 (2010).

    Article  CAS  Google Scholar 

  10. Du Pasquier, L. Meeting the demand for innate and adaptive immunities during evolution. Scand. J. Immunol. 62 (Suppl. 1), 39–48 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Herrin, B. R. & Cooper, M. D. Alternative adaptive immunity in jawless vertebrates. J. Immunol. 185, 1367–1374 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Litman, G. W., Rast, J. P. & Fugmann, S. D. The origins of vertebrate adaptive immunity. Nature Rev. Immunol. 10, 543–553 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Cannon, J. P. et al. Recognition of additional roles for immunoglobulin domains in immune function. Semin. Immunol. 22, 17–24 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Litman, G. W., Dishaw, L. J., Cannon, J. P., Haire, R. N. & Rast, J. P. Alternative mechanisms of immune receptor diversity. Curr. Opin. Immunol. 19, 526–534 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. Bajoghli, B. et al. A thymus candidate in lampreys. Nature 470, 90–94 (2011). This paper shows that the sites of development of the two lymphocyte lineages in lampreys are anatomically distinct and suggests that a thymus equivalent is situated in the gill basket.

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Kasamatsu, J. et al. Identification of a third variable lymphocyte receptor in the lamprey. Proc. Natl Acad. Sci. USA 107, 14304–14308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cooper, M. D., Peterson, R. D. & Good, R. A. Delineation of the thymic and bursal lymphoid systems in the chicken. Nature 205, 143–146 (1965). This paper introduced the concept of the dual nature of the vertebrate immune system, that is, the presence of functionally distinct B and T cell lineages.

    Article  CAS  PubMed  Google Scholar 

  27. Dias, S., Xu, W., McGregor, S. & Kee, B. Transcriptional regulation of lymphocyte development. Curr. Opin. Genet. Dev. 18, 441–448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ramírez, J., Lukin, K. & Hagman, J. From hematopoietic progenitors to B cells: mechanisms of lineage restriction and commitment. Curr. Opin. Immunol. 22, 177–184 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Rothenberg, E. V., Zhang, J. & Li, L. Multilayered specification of the T-cell lineage fate. Immunol. Rev. 238, 150–168 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Martin, F. & Kearney, J. F. B1 cells: similarities and differences with other B cell subsets. Curr. Opin. Immunol. 13, 195–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Yamagata, T., Benoist, C. & Mathis, D. A shared gene-expression signature in innate-like lymphocytes. Immunol. Rev. 210, 52–66 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Yoshimoto, M. et al. Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proc. Natl Acad. Sci. USA 108, 1468–1473 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schorpp, M. et al. Conserved functions of Ikaros in vertebrate lymphocyte development: genetic evidence for distinct larval and adult phases of T cell development and two lineages of B cells in zebrafish. J. Immunol. 177, 2463–2476 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, Y. A. et al. IgT, a primitive immunoglobulin class specialized in mucosal immunity. Nature Immunol. 11, 827–835 (2010).

    Article  CAS  Google Scholar 

  35. 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 

  36. Ciofani, M. & Zúñiga-Pflücker, J. C. Determining γδ versus αβ T cell development. Nature Rev. Immunol. 10, 657–663 (2010).

    Article  CAS  Google Scholar 

  37. Kreslavsky, T., Gleimer, M. & von Boehmer, H. αβ versus γδ lineage choice at the first TCR-controlled checkpoint. Curr. Opin. Immunol. 22, 185–192 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 

  39. Cooper, M. A. & Yokoyama, W. M. Memory-like responses of natural killer cells. Immunol. Rev. 235, 297–305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Höglund, P. & Brodin, P. Current perspectives of natural killer cell education by MHC class I molecules. Nature Rev. Immunol. 10, 724–734 (2010).

    Article  CAS  Google Scholar 

  41. Raulet, D. H., Vance, R. E. & McMahon, C. W. Regulation of the natural killer cell receptor repertoire. Annu. Rev. Immunol. 19, 291–330 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Sun, J. C., Beilke, J. N. & Lanier, L. L. Immune memory redefined: characterizing the longevity of natural killer cells. Immunol. Rev. 236, 83–94 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Van de Peer, Y., Maere, S. & Meyer, A. The evolutionary significance of ancient genome duplications. Nature Rev. Genet. 10, 725–732 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Okada, K. & Asai, K. Expansion of signaling genes for adaptive immune system evolution in early vertebrates. BMC Genomics 9, 218 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Kawamoto, H. & Katsura, Y. A new paradigm for hematopoietic cell lineages: revision of the classical concept of the myeloid–lymphoid dichotomy. Trends Immunol. 30, 193–200 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Han, Y. et al. The primitive immune system of amphioxus provides insights into the ancestral structure of the vertebrate immune system. Dev. Comp. Immunol. 34, 791–796 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Ballarin, L. & Cima, F. Cytochemical properties of Botryllus schlosseri haemocytes: indications for morpho-functional characterisation. Eur. J. Histochem. 49, 255–264 (2005).

    CAS  PubMed  Google Scholar 

  49. Leclerc, M., Brillouet, C. & Luquet, G. The starfish axial organ: an ancestral lymphoid organ. Dev. Comp. Immunol. 4, 605–615 (1980).

    Article  CAS  PubMed  Google Scholar 

  50. Davis, M. M. & Bjorkman, P. J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395–402 (1988). Based on the structure of peptide–MHC–TCR complexes, this paper proposes a model of how TCRs and BCRs have evolved.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vettermann, C. & Schlissel, M. S. Allelic exclusion of immunoglobulin genes: models and mechanisms. Immunol. Rev. 237, 22–42 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Krangel, M. S. Mechanics of T cell receptor gene rearrangement. Curr. Opin. Immunol. 21, 133–139 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Reynaud, C. A., Bertocci, B., Dahan, A. & Weill, J. C. Formation of the chicken B-cell repertoire: ontogenesis, regulation of Ig gene rearrangement, and diversification by gene conversion. Adv. Immunol. 57, 353–378 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Chaudhuri, J. et al. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv. Immunol. 94, 157–214 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. 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 

  59. Zhang, S.-M., Adema, C. M., Kepler, T. B. & Loker, E. S. Diversification of Ig superfamily genes in an invertebrate. Science 305, 251–254 (2004). This paper provides evidence for somatic diversification of immune-related receptors in an invertebrate.

    Article  CAS  PubMed  Google Scholar 

  60. Hamilton, C. E., Papavasiliou, F. N. & Rosenberg, B. R. Diverse functions for DNA and RNA editing in the immune system. RNA Biol. 7, 220–228 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Ghosh, J. et al. Sp185/333: a novel family of genes and proteins involved in the purple sea urchin immune response. Dev. Comp. Immunol. 34, 235–245 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. 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 

  63. van Meerwijk, J. P. M. et al. Quantitative impact of thymic clonal deletion on the T cell repertoire. J. Exp. Med. 185, 377–383 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. 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 

  66. 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 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Cho, J.-H., Kim, H.-O., Surh, C. D. & Sprent, J. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32, 214–226 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Anderson, G., Lane, P. J. L. & Jenkinson, E. J. Generating intrathymic microenvironments to establish T-cell tolerance. Nature Rev. Immunol. 7, 954–963 (2007).

    Article  CAS  Google Scholar 

  71. Bleul, C. C. et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992–996 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Rossi, S. W., Jenkinson, W. E., Anderson, G. & Jenkinson, E. J. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988–991 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Jenkins, M. K., Chu, H. H., McLachlan, J. B. & Moon, J. J. On the composition of the preimmune repertoire of T cells specific for peptide–major histocompatibility complex ligands. Annu. Rev. Immunol. 28, 275–294 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. 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 study used in vitro selection to identify VLRA proteins that directly bind to unprocessed protein antigens with high affinity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dervovi, D. & Zúñiga-Pflücker, J. C. Positive selection of T cells, an in vitro view. Semin. Immunol. 22, 276–286 (2010).

    Article  CAS  Google Scholar 

  77. Huseby, E. S. et al. How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Scott-Browne, J. P., White, J., Kappler, J. W., Gapin, L. & Marrack, P. Germline-encoded amino acids in the αβ T-cell receptor control thymic selection. Nature 458, 1043–1046 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, B. et al. A single peptide–MHC complex positively selects a diverse and specific CD8 T cell repertoire. Science 326, 871–874 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Palmer, E. Negative selection — clearing out the bad apples from the T-cell repertoire. Nature Rev. Immunol. 3, 383–391 (2003).

    Article  CAS  Google Scholar 

  81. Derbinski, J. & Kyewski, B. How thymic antigen presenting cells sample the body's self-antigens. Curr. Opin. Immunol. 22, 592–600 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Josefowicz, S. Z. & Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30, 616–625 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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 

  84. Corbeaux, T. et al. Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc. Natl Acad. Sci. USA 107, 16613–16618 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nehls, M. et al. Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886–889 (1996). This paper shows that the FOXN1 transcription factor is required for the differentiation of thymic epithelial cells.

    Article  CAS  PubMed  Google Scholar 

  86. Bleul, C. C. & Boehm, T. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30, 3371–3379 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Klein, J. & Nikolaidis, N. The descent of the antibody-based immune system by gradual evolution. Proc. Natl Acad. Sci. USA 102, 169–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Boehm, T. Quality control in self/nonself discrimination. Cell 125, 845–858 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Dishaw, L. J. & Litman, G. W. Invertebrate allorecognition: the origins of histocompatibility. Curr. Biol. 19, R286–R288 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McKitrick, T. R. & De Tomaso, A. W. Molecular mechanisms of allorecognition in a basal chordate. Semin. Immunol. 22, 34–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Rosengarten, R. D. & Nicotra, M. L. Model systems of invertebrate allorecognition. Curr. Biol. 21, R82–R92 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Perlot, T. & Alt, F. W. Cis-regulatory elements and epigenetic changes control genomic rearrangements of the IgH locus. Adv. Immunol. 99, 1–32 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Spicuglia, S., Pekowska, A., Zacarias-Cabeza, J. & Ferrier, P. Epigenetic control of Tcrb gene rearrangement. Semin. Immunol. 22, 330–336 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Kaufman, J., Skjoedt, K. & Salomonsen, J. The MHC molecules of nonmammalian vertebrates. Immunol. Rev. 113, 83–117 (1990).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  96. Leinders-Zufall, T. et al. MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306, 1033–1037 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Leinders-Zufall, T., Ishii, T., Mombaerts, P., Zufall, F. & Boehm, T. Structural requirements for the activation of mouse vomeronasal sensory neurons by MHC peptides. Nature Neurosci. 12, 1551–1558 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Milinski, M. et al. Mate choice decisions of stickleback females predictably modified by MHC peptide ligands. Proc. Natl Acad. Sci. USA 102, 4414–4418 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jin, M. S. & Lee, J.-O. Structures of TLR–ligand complexes. Curr. Opin. Immunol. 20, 414–419 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Kim, H. M. et al. Crystal structure of the TLR4–MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130, 906–917 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. 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 

  102. Kim, H. M. et al. Structural diversity of the hagfish variable lymphocyte receptors. J. Biol. Chem. 282, 6726–6732 (2007).

    CAS  PubMed  Google Scholar 

  103. Vyas, J. M., Van der Veen, A. G. & Ploegh, H. L. The known unknowns of antigen processing and presentation. Nature Rev. Immunol. 8, 607–618 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I apologize to all of my colleagues whose work could not be cited directly, owing to space constraints. I thank members of my group for their contributions and insightful discussions and T. Manke for help with the preparation of the figure shown in Supplementary information S2. This work was supported by grants from the Max Planck Society, the European Union and the Deutsche Forschungsgemeinschaft.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Supplementary information S1 (box)

“Proto-adaptive” immune systems (PDF 81 kb)

Suplementary information S2 (box)

An evolutionary footprint on somatically diversifying genes encoding potentially self-reactive antigen receptors (PDF 211 kb)

Related links

Related links

FURTHER INFORMATION

Thomas Boehm's homepage

Glossary

Variable lymphocyte receptors

(VLRs). Alternative forms of somatically diversified antigen receptors expressed by lymphocytes of jawless vertebrates. The combinatorial diversity of VLRs is based on variable numbers of leucine-rich repeat elements assembled by a gene conversion process.

Somatic diversification

Changes in DNA sequence that occur in individual cells and their progeny. Traditionally, this process has been associated with lymphocytes and is brought about during gene rearrangements, as well as through gene conversion and somatic hypermutation.

Proto-adaptive immune systems

Immune systems of invertebrates that have many of the characteristics of the adaptive immune systems of vertebrates, such as selective expression of individual members of immune receptor gene families and limited somatic diversification.

B1 and B2 cells

B1 cells are the minority population of B cells. These cells express CD5, respond quickly to antigen, produce antibodies of broad specificity and do not depend on MHC class II-mediated T cell help.B2 cells are the main population of B cells. These cells do not express CD5, respond more slowly to antigen than B1 cells, produce antibodies of narrow specificity and depend on MHC class II-mediated T cell help.

Teleosts

A group of jawed vertebrates to which most living bony fish belong. Popular model species are Danio rerio (zebrafish) and Oryzias latipes (medaka).

Natural killer cells

Lymphocytes that confer innate immunity. They were originally defined on the basis of their cytolytic activity against tumour targets, but it is now recognized that they serve a broader role in host defence against invading pathogens.

Whole-genome duplication

The duplication of an entire genome is considered to have a major role in evolution, because it generates paralogues of each gene that can then assume new functions.

Ur-lymphocyte

A hypothetical ancestral lymphocyte of invertebrates from which the functionally distinct lymphocyte lineages of vertebrates have evolved.

Deuterostome

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).

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both B cell and T cell receptors.

Recombination activating gene

(RAG). A protein involved in creating the double strand DNA breaks necessary for producing the rearranged gene segments that encode the complete protein chains of B cell and T cell receptors.

Translocon configuration

An antigen receptor gene structure in which many variable, diversity and joining elements occur together with one single constant region element.

Combinatorial diversity

A form of sequence variation that occurs when one each of many genetic elements, for example variable and joining elements, are fused together during the process of somatic rearrangement of antigen receptor genes. This is an important source of sequence variability in all antigen receptors of vertebrates.

Junctional diversity

A form of sequence variation that occurs when different genetic elements, for example variable and joining elements, are fused together by an error-prone DNA repair mechanism, such as non-homologous end joining. This is one of the sources of diversity generated by V(D)J recombination, the other being combinatorial diversity.

Allelic exclusion

In theory, every B cell has the potential to produce two immunoglobulin heavy chains and two immunoglobulin light chains. In practice, however, a B cell produces only one immunoglobulin heavy chain and most produce only one immunoglobulin light chain. Similarly, most T cells produce only a single TCRβ protein. The process by which the production of two different chains is prevented is known as allelic exclusion. Allelic exclusion is accomplished primarily through regulated V(D)J recombination.

Notch

A transmembrane receptor involved in the pathway for direct cell–cell signalling through its association with a transmembrane ligand of the Delta or Serrate (jagged) family on a neighbouring cell. The large intracellular domain of Notch is cleaved and travels to the nucleus to become a direct co-activator of the transcription factor RBPJ (also known as CSL).

Alloreactivity

The process of responding to antigens that are distinct between members of the same species, such as MHC molecules or blood group antigens.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boehm, T. Design principles of adaptive immune systems. Nat Rev Immunol 11, 307–317 (2011). https://doi.org/10.1038/nri2944

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2944

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing