Nothing Special   »   [go: up one dir, main page]
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.

  • Viewpoint
  • Published:

Reflections on the clonal-selection theory

Nature Reviews Immunology volume 7, pages 823–830 (2007)Cite this article

Abstract

How do we account for the immune system's ability to produce antibodies in response to new antigens? It has been 50 years since F. Macfarlane Burnet published his answer to this question: the clonal-selection theory of antibody diversity. The idea that specificity for diverse antigens exists before these antigens are encountered was a radical notion at the time, but one that became widely accepted. In this article, Nature Reviews Immunology asks six key scientists for their thoughts and opinions on the clonal-selection theory, from its first proposal to their views of it today.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. 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 

  2. Burnet, F. M. The mechanism of immunity. Sci. Amer. 204, 158–164 (1961).

    Article  Google Scholar 

  3. Luria S. E. & Delbrück, M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28, 491–511 (1943).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Newcombe, H. Origin of bacterial variants. Nature 164, 150–151 (1949).

    Article  CAS  Google Scholar 

  5. Lederberg, J. & Lederberg, E. M. Replica plating and indirect selection of bacterial mutants. J. Bacteriol. 63, 399–406 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Jerne, N. K. The natural selection theory of antibody formation. Proc. Natl Acad. Sci. USA 41, 849–857 (1955).

    Article  CAS  Google Scholar 

  7. Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (Cambridge Univ. Press, Cambridge, 1959).

    Book  Google Scholar 

  8. Talmage, D. W. Allergy and immunology. Annu. Rev. Med. 8, 239–256 (1957).

    Article  CAS  Google Scholar 

  9. Ehrlich, P. On immunity with special reference to cell life. Proc. R. Soc. 66, 424–428 (1900).

    Article  CAS  Google Scholar 

  10. Burnet, F. M. & Fenner, F. The Production of Antibodies 2nd edn (Macmillan and Co., Melbourne, 1949).

    Google Scholar 

  11. Owen, R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102, 400–401 (1945).

    Article  CAS  Google Scholar 

  12. Lederberg, J. Genes and antibodies: do antigens bear instructions for antibody specificity or do they select cell lines that arise by mutation? Science 129, 1649–1653 (1959).

    Article  CAS  Google Scholar 

  13. Burnet, F. M. The clonal selection theory of acquired immunity — a Darwinian modification. Aust. J. Sci. 27, 6–7 (1964).

    Google Scholar 

  14. Bretscher, P. A. & Cohn, M. Minimal model for the mechanism of antibody induction and paralysis by antigen. Nature 220, 444–448 (1968).

    Article  CAS  Google Scholar 

  15. Bretscher, P. & Cohn, M. A theory of self–nonself discrimination. Science 169, 1042–1049 (1970).

    Article  CAS  Google Scholar 

  16. Talmage, D. W. Immunological specificity: unique combinations of selected natural globulins provide an alternative to the classical concept. Science 129, 1643–1648 (1959).

    Article  CAS  Google Scholar 

  17. Szilard, L. The molecular basis of antibody formation. Proc. Natl Acad. Sci. USA 46, 293–302 (1960).

    Article  CAS  Google Scholar 

  18. Szilard, L. The control of the formation of specific proteins in bacteria and in animal cells. Proc. Natl Acad. Sci. USA 46, 277–292 (1960).

    Article  CAS  Google Scholar 

  19. Nossal, G. J. V. & Lederberg, J. Antibody production by single cells. Nature 181, 1419–1420 (1958).

    Article  CAS  Google Scholar 

  20. Attardi, G., Cohn, M., Horibata, K. & Lennox, E. S. Antibody formation by rabbit lymph node cells. I. Single cell responses to several antigens. J. Immunol. 92, 335–345 (1964).

    CAS  PubMed  Google Scholar 

  21. Jerne, N. K. & Nordin, A. A. Plaque formation in agar by single antibody-producing cells. Science 140, 405 (1963).

    Article  Google Scholar 

  22. Nossal, G. J. V. & Mäkelä, O. Elaboration of antibodies by single cells. Annu. Rev. Microbiol. 16, 53–74 (1962).

    Article  CAS  Google Scholar 

  23. Warner, N. L. Szenberg, A. & Burnet, F. M. The immunological role of different lymphoid organs in the chicken. I. Dissociation of immunological responsiveness. Aust. J. Exp. Biol. Med. Sci. 40, 373–387 (1962).

    Article  CAS  Google Scholar 

  24. Trentin, J. & Fahlberg, W. J. in Conceptual Advances in Immunology and Oncology 66–74 (Hoeber-Harper, New York, 1963).

    Google Scholar 

  25. Burnet, F. M. in Conceptual Advances in Immunology and Oncology 72 (Hoeber-Harper, New York, 1963).

    Google Scholar 

  26. Burnet, F. M. in Molecular and Cellular Basis of Antibody Formation 653 (Czech Academy of Sciences, Prague, 1965).

    Google Scholar 

  27. Burnet, F. M. Impact on ideas of immunology. Cold Spring Harbor Symp. Quant. Biol. 32, 1 (1967).

    Article  CAS  Google Scholar 

  28. Šterzl, J. & Silverstein, A. M. Developmental aspects of immunity. Adv. Immunol. 6, 337–459 (1966).

    Article  Google Scholar 

  29. Sigal, N. H. & Klinman, N. R. The B-cell clonotype repertoire. Adv. Immunol. 26, 255–337 (1978).

    Article  CAS  Google Scholar 

  30. Cohn, M., Monod, J., Pollock. M. R., Spiegelman, S. & Stanier, R. Y. Terminology of enzyme formation. Nature 172, 1096 (1953).

    Article  CAS  Google Scholar 

  31. Landsteiner, K. The Specificity of Serological Reactions (Harvard University Press, Cambridge, 1946).

    Google Scholar 

  32. Watson, J. D. & Crick, F. H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171, 737–738 (1953).

    Article  CAS  Google Scholar 

  33. Billingham, R. E., Brent, L., Medawar, P. B. Actively acquired tolerance of foreign cells. Nature 172, 603–606 (1953).

    Article  CAS  Google Scholar 

  34. Dixon, F. J., Talmage, D. W. & Maurer, P. H. Radiosensitive and radioresistant phases in the antibody response. J. Immunol. 68, 693–700 (1952).

    CAS  PubMed  Google Scholar 

  35. Putnam, F. W. & Udin, R. Proteins in multiple myeloma. I. Physicochemical study of serum proteins. J. Biol. Chem. 202, 702–743 (1953).

    Google Scholar 

  36. Taliaferro, W. H. & Taliaferro, L. G. The dynamics of hemolysin formation in intact and splenectomized rabbits. J. Infect. Dis. 87, 37–42 (1950).

    Article  CAS  Google Scholar 

  37. Merton, R. K. On The Shoulders Of Giants (University of Chicago Press, Chicago, 1965).

    Google Scholar 

  38. Nossal, G. J. V. One cell, one antibody: prelude and aftermath. Immunol. Rev. 185, 15–23 (2002).

    Article  CAS  Google Scholar 

  39. Mäkelä, O. & Karjalainen, K. Inherited immunoglobulin idiotypes of the mouse. Immunol. Rev. 34, 119–138 (1977).

    Article  Google Scholar 

  40. Pauling, L. A theory of the structure and process of formation of antibodies. J. Am. Chem. Soc. 62, 2643–2657 (1940).

    Article  CAS  Google Scholar 

  41. Edelman, G. M. Dissociation of γ-globulin. J. Am. Chem. Soc. 81, 3155–3156 (1959).

    Article  CAS  Google Scholar 

  42. Hilschmann, N. & Craig, L. C. Amino acid sequence studies with Bence-Jones proteins. Proc. Natl Acad. Sci. USA 53, 1403–1409 (1965).

    Article  CAS  Google Scholar 

  43. Edelman, G. Antibody structure and molecular immunology. Ann. NY Acad. Sci. 190, 5–25 (1971).

    Article  CAS  Google Scholar 

  44. Porter, R. R. Structural studies of immunoglobulins. Science 180, 713–716 (1973).

    Article  CAS  Google Scholar 

  45. Tonegawa, S. Somatic generation of immune diversity. In Vitro Cell. Dev. Biol. 24, 253–265 (1988).

    Article  CAS  Google Scholar 

  46. Kim, S., Davis, M., Sinn, E., Patten, P. & Hood, L. Antibody diversity: somatic hypermutation of rearranged VH genes. Cell 27, 573–581 (1981).

    Article  CAS  Google Scholar 

  47. Weigert, M. G., Cesari, I. M., Yonkovich, S. J. & Cohn, M. Variability in the λ light chain sequences of mouse antibody. Nature 228, 1045–1047 (1970).

    Article  CAS  Google Scholar 

  48. Wu, T. T. & Kabat, E. A. An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132, 211–250 (1970).

    Article  CAS  Google Scholar 

  49. Bussard, A. Darwinisme et immunologie. Bull. Soc. Fran. Philosophie 77, 1 (1982) (in French).

    Google Scholar 

  50. Silverstein, A. M. The clonal selection theory: what it really is and why modern challenges are misplaced. Nature Immunol. 3, 793–796 (2002).

    Article  CAS  Google Scholar 

  51. Cohen, I. R. The cognitive paradigm and the immunological homunculus. Immunol. Today 13, 490–494 (1992).

    Article  CAS  Google Scholar 

  52. Cohen, I. R. Tending Adam's Garden 1–296 (Academic Press, San Diego, 2000).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  54. Burnet, F. M. Self and Not-self (Cambridge University Press, Cambridge, 1969).

    Google Scholar 

  55. Silverstein, A. M. & Rose, N. R. On the mystique of the immunological self. Immunol. Rev. 159, 197–206 (1997).

    Article  CAS  Google Scholar 

  56. Attardi, G., Cohn, M., Horibata, K. & Lennox, E. S. Antibody formation by rabbit lymph node cells. II. Further observations on the behavior of single antibody-producing cells with respect to their synthetic capacity and morphology. J. Immunol. 92, 346–555 (1964).

    CAS  PubMed  Google Scholar 

  57. Attardi, G., Cohn, M., Horibata, K. & Lennox, E. S. Antibody formation by rabbit lymph node cells. III. The controls for microdrop and micropipet experiments. J. Immunol. 92, 356–371 (1964).

    CAS  PubMed  Google Scholar 

  58. Attardi, G., Cohn, M., Horibata, K. & Lennox, E. S. Antibody formation by rabbit lymph node cells. IV. The detailed methods for measuring antibody synthesis by individual cells, the kinetics of antibody formation by rabbits and the properties of cell suspensions. J. Immunol. 92, 372–390 (1964).

    CAS  PubMed  Google Scholar 

  59. Attardi, G., Cohn, M., Horibata, K. & Lennox, E. S. Antibody formation by rabbit lymph node cells. V. Cellular heterogeneity in the production of antibody to T5. J. Immunol. 93, 94–95 (1964).

    CAS  PubMed  Google Scholar 

  60. Raff, M. C., Feldmann, M. & de Petris, S. Monospecificity of bone marrow-derived lymphocytes. J. Exp. Med. 137, 1024–1030 (1973).

    Article  CAS  Google Scholar 

  61. Attardi, G., Cohn, M., Horibata, K. & Lennox, E. S. Symposium on the biology of cells modified by viruses or antigens. II. On the analysis of antibody synthesis at the cellular level. Bact. Rev. 23, 213–223 (1959).

    CAS  PubMed  Google Scholar 

  62. Casellas, R. et al. Contribution of receptor editing to the antibody repertoire. Science 291, 1541–1544 (2001).

    Article  CAS  Google Scholar 

  63. Fraenkel, S. et al. Allelic choice governs somatic hypermutation in vivo at the immunoglobulin k-chain locus. Nature Immunol. 8, 715–722 (2007).

    Article  CAS  Google Scholar 

  64. Malissen, M. J., et al. Regulation of TCRα and β allelic exclusion during T cell development. Immunol. Today 13, 315–322 (1992).

    Article  CAS  Google Scholar 

  65. Cunningham, A. J. in The Generation of Antibody Diversity (ed. Cunningham, A. J.) 69–104 (Academic Press, London, 1976)

    Google Scholar 

  66. McKean, D. K., Staudt, L., Gerhard, W. & Weigert, M. Generation of antibody diversity in the immune response to Influenza. Proc. Natl Acad. Sci. USA 81, 3180–3186 (1984).

    Article  CAS  Google Scholar 

  67. Cohn, M., Langman, R. E. & Mata, J. A computerized model for the self-nonself discrimination at the level of the T-helper (Th genesis). I. The origin of “primer” effector T-helpers. Int. Immunol. 14, 1105–1112 (2002).

    Article  CAS  Google Scholar 

  68. Langman, R. E., Mata, J. & Cohn, M. A computerized model for the self–nonself discrimination at the level of the T-helper (Th genesis) II. The behavior of the system upon encounter with nonself antigens. Int. Immunol. 15, 593–609 (2003).

    Article  CAS  Google Scholar 

  69. Miller, J. Self–Nonself discrimination by T lymphocytes. C. R. Biol. 327, 399–408 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  71. Langman, R. E. & Cohn, M. The E–T (elephant–tadpole) paradox necessitates the concept of a unit of B-cell function: the protection. Mol. Immunol. 24, 675–697 (1987).

    Article  CAS  Google Scholar 

  72. Cohn, M. & Langman, R. E. The protecton: the unit of humoral immunity selected by evolution. Immunol. Rev. 115, 11–142 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  74. Witsch, E. J., Cao, H., Fukuyama, H. & Weigert, M. Light chain generates polyreactive antibodies in chronic graft-versus-host reaction. J. Exp. Med. 203, 1761–1772 (2006).

    Article  CAS  Google Scholar 

  75. Li, Y., Li, H. & Weigert, M. Autoreactive B cells in the marginal zone that express dual receptors. J. Exp. Med. 195, 181–188 (2002).

    Article  CAS  Google Scholar 

Download references

Authors
  1. Melvin Cohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Av Mitchison
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William E. Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arthur M. Silverstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David W. Talmage
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Weigert
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

1960 Nobel Prize in Physiology or Medicine

1984 Nobel Prize in Physiology or Medicine

Melvin Cohn's homepage

William E. Paul's homepage

David W. Talmage's homepage

Martin Weigert's homepage

Glossary

Instructionist theory

The theory that antigen acts as a template to instruct antibody specificity and production, so that antibodies are manufactured in the body de novo in response to a foreign antigen.

Selectionist theory

The theory that the individual has a pre-formed repertoire of antibodies, and that the binding of antigen to antibody triggers the self-replication of the bound antibody (that is, the antigen selects for the antibody).

Clonal-selection theory

(CST). The theory that each B cell has membrane-bound antibody receptors that are specific for one particular antigen, and once an antibody is selected (bound) by an antigen, the cell is stimulated to produce a clone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cohn, M., Av Mitchison, N., Paul, W. et al. Reflections on the clonal-selection theory. Nat Rev Immunol 7, 823–830 (2007). https://doi.org/10.1038/nri2177

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2177

This article is cited by

Search

Advanced 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