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Dual nature of the adaptive immune system in lampreys

Nature volume 459, pages 796–801 (2009)Cite this article

A Corrigendum to this article was published on 20 August 2009

Abstract

Jawless vertebrates use variable lymphocyte receptors (VLR) comprised of leucine-rich-repeat (LRR) segments as counterparts of the immunoglobulin-based receptors that jawed vertebrates use for antigen recognition. Highly diverse VLR genes are somatically assembled by the insertion of variable LRR sequences into incomplete germline VLRA and VLRB genes. Here we show that in sea lampreys (Petromyzon marinus) VLRA and VLRB anticipatory receptors are expressed by separate lymphocyte populations by monoallelic VLRA or VLRB assembly, together with expression of cytosine deaminase 1 (CDA1) or 2 (CDA2), respectively. Distinctive gene expression profiles for VLRA+ and VLRB+ lymphocytes resemble those of mammalian T and B cells. Although both the VLRA and the VLRB cells proliferate in response to antigenic stimulation, only the VLRB lymphocytes bind native antigens and differentiate into VLR antibody-secreting cells. Conversely, VLRA lymphocytes respond preferentially to a classical T-cell mitogen and upregulate the expression of the pro-inflammatory cytokine genes interleukin-17 (IL-17) and macrophage migration inhibitory factor (MIF). The finding of T-like and B-like lymphocytes in lampreys offers new insight into the evolution of adaptive immunity.

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Figure 1: VLRA and VLRB expression define distinct lymphocyte populations.
Figure 2: Monoallelic assembly of VLRA and VLRB genes.
Figure 3: Differential gene expression profiles of VLRA + and VLRB + lymphocytes.
Figure 4: Antigen-activated VLRA + lymphocytes do not secrete their receptors.
Figure 5: PHA preferentially stimulates VLRA + lymphocytes.

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References

  1. Paul, W. E. Fundamental Immunology 6th edn (Lippincott Williams & Wilkins, 2008)

    Google Scholar 

  2. 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)

    Article  ADS  CAS  Google Scholar 

  3. Roitt, I. M., Greaves, M. F., Torrigiani, G., Brostoff, J. & Playfair, J. H. The cellular basis of immunological responses. A synthesis of some current views. Lancet 2, 367–371 (1969)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  5. Yanagi, Y. et al. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145–149 (1984)

    Article  ADS  CAS  Google Scholar 

  6. Hedrick, S. M., Cohen, D. I., Nielsen, E. A. & Davis, M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149–153 (1984)

    Article  ADS  CAS  Google Scholar 

  7. Jung, D., Giallourakis, C., Mostoslavsky, R. & Alt, F. W. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu. Rev. Immunol. 24, 541–570 (2006)

    Article  CAS  Google Scholar 

  8. Burnet, F. M. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust. J. Sci. 20, 67–69 (1957)

    Google Scholar 

  9. Zinkernagel, R. M. & Doherty, P. C. Cytotoxic thymus-derived lymphocytes in cerebrospinal fluid of mice with lymphocytic choriomeningitis. J. Exp. Med. 138, 1266–1269 (1973)

    Article  CAS  Google Scholar 

  10. Nikolic-Zugic, J. & Bevan, M. J. Role of self-peptides in positively selecting the T-cell repertoire. Nature 344, 65–67 (1990)

    Article  ADS  CAS  Google Scholar 

  11. von Boehmer, H. Selection of the T-cell repertoire: receptor-controlled checkpoints in T-cell development. Adv. Immunol. 84, 201–238 (2004)

    Article  CAS  Google Scholar 

  12. Unanue, E. R. Perspective on antigen processing and presentation. Immunol. Rev. 185, 86–102 (2002)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. 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 

  15. 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  Google Scholar 

  16. Ardavin, C. F. & Zapata, A. The pharyngeal lymphoid tissue of lampreys. A morpho-functional equivalent of the vertebrate thymus? Thymus 11, 59–65 (1988)

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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  ADS  CAS  Google Scholar 

  19. Pancer, Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  21. 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 

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

    Article  ADS  CAS  Google Scholar 

  23. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  27. Ho, I. C., Tai, T. S. & Pai, S. Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nature Rev. Immunol. 9, 125–135 (2009)

    Article  CAS  Google Scholar 

  28. Suzuki, T., Shin, I. T., Kohara, Y. & Kasahara, M. Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes. Dev. Comp. Immunol. 28, 993–1003 (2004)

    Article  Google Scholar 

  29. Banerjee, D., Liou, H. C. & Sen, R. c-Rel-dependent priming of naive T cells by inflammatory cytokines. Immunity 23, 445–458 (2005)

    Article  CAS  Google Scholar 

  30. Quintana, F. J. et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008)

    Article  ADS  CAS  Google Scholar 

  31. Wakabayashi, Y. et al. Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Nature Immunol. 4, 533–539 (2003)

    Article  CAS  Google Scholar 

  32. Liu, C. et al. Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood 108, 2531–2539 (2006)

    Article  CAS  Google Scholar 

  33. Maillard, I., Fang, T. & Pear, W. S. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu. Rev. Immunol. 23, 945–974 (2005)

    Article  CAS  Google Scholar 

  34. Kishihara, K. et al. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74, 143–156 (1993)

    Article  CAS  Google Scholar 

  35. Lippert, U., Zachmann, K., Henz, B. M. & Neumann, C. Human T lymphocytes and mast cells differentially express and regulate extra- and intracellular CXCR1 and CXCR2. Exp. Dermatol. 13, 520–525 (2004)

    Article  CAS  Google Scholar 

  36. Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007)

    Article  CAS  Google Scholar 

  37. Tsutsui, S., Nakamura, O. & Watanabe, T. Lamprey (Lethenteron japonicum) IL-17 upregulated by LPS-stimulation in the skin cells. Immunogenetics 59, 873–882 (2007)

    Article  CAS  Google Scholar 

  38. Bloom, B. R. & Shevach, E. Requirement for T cells in the production of migration inhibitory factor. J. Exp. Med. 142, 1306–1311 (1975)

    Article  CAS  Google Scholar 

  39. Weiser, W. Y. et al. Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc. Natl Acad. Sci. USA 86, 7522–7526 (1989)

    Article  ADS  CAS  Google Scholar 

  40. Ma, Q., Jones, D. & Springer, T. A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463–471 (1999)

    Article  CAS  Google Scholar 

  41. Murphy, K. M., Nelson, C. A. & Sedy, J. R. Balancing co-stimulation and inhibition with BTLA and HVEM. Nature Rev. Immunol. 6, 671–681 (2006). 7

    Article  CAS  Google Scholar 

  42. Jumaa, H., Hendriks, R. W. & Reth, M. B cell signaling and tumorigenesis. Annu. Rev. Immunol. 23, 415–445 (2005)

    Article  CAS  Google Scholar 

  43. Okada, T., Maeda, A., Iwamatsu, A., Gotoh, K. & Kurosaki, T. BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 13, 817–827 (2000)

    Article  CAS  Google Scholar 

  44. Yu, C., Ehrhardt, G. R., Alder, M. N., Cooper, M. D. & Xu, A. Inhibitory signaling potential of a TCR-like molecule in lamprey. Eur. J. Immunol. 39, 571–579 (2009)

    Article  CAS  Google Scholar 

  45. Sims-Mourtada, J. C. et al. In vivo expression of interleukin-8, and regulated on activation, normal, T-cell expressed, and secreted, by human germinal centre B lymphocytes. Immunology 110, 296–303 (2003)

    Article  CAS  Google Scholar 

  46. Pasare, C. & Medzhitov, R. Control of B-cell responses by Toll-like receptors. Nature 438, 364–368 (2005)

    Article  ADS  CAS  Google Scholar 

  47. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006)

    Article  CAS  Google Scholar 

  48. Ishii, A. et al. Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors. J. Immunol. 178, 397–406 (2007)

    Article  CAS  Google Scholar 

  49. De Tomaso, A. W. et al. Isolation and characterization of a protochordate histocompatibility locus. Nature 438, 454–459 (2005)

    Article  ADS  CAS  Google Scholar 

  50. Putnam, N. H. et al. The amphioxus genome and the evolution of the chordate karyotype. Nature 453, 1064–1071 (2008)

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank M. N. Alder and G. R. A. Ehrhardt for suggestions and discussion; C. L. Turnbough, Jr for providing B. anthracis spores and exosporium; D. E. Briles and W. H. Benjamin, Jr for E. coli, S. pneumoniae and S. typhimurium; H. Yi for help with electron microscopy; S. A. Durham and R. E. Karaffa, II for help with cell sorting; M. Flurry for help with preparation of figures. This work is supported by the National Institutes of Health and the Georgia Research Alliance.

Author Contributions P.G., M.H., B.R.H., J.L., C.Y., A.S. and M.D.C. designed the research, analysed data and wrote the paper; P.G., M.H., B.R.H., J.L., C.Y. and A.S. performed the research.

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  1. Peng Guo, Masayuki Hirano and Brantley R. Herrin: These authors contributed equally to this work.

Authors and Affiliations

  1. Emory Vaccine Center and Department of Pathology and Laboratory Medicine, Emory University, 1462 Clifton Road North-East, Atlanta, Georgia 30322, USA,

    Peng Guo, Masayuki Hirano, Brantley R. Herrin, Jianxu Li, Cuiling Yu, Andrea Sadlonova & Max D. Cooper

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Correspondence to Max D. Cooper.

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Guo, P., Hirano, M., Herrin, B. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009). https://doi.org/10.1038/nature08068

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