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.

  • Essay
  • Published:

The speed of change: towards a discontinuity theory of immunity?

Nature Reviews Immunology volume 13, pages 764–769 (2013)Cite this article

Subjects

Abstract

Immunology — though deeply experimental in everyday practice — is also a theoretical discipline. Recent advances in the understanding of innate immunity, how it is triggered and how it shares features that have previously been uniquely ascribed to the adaptive immune system, can contribute to the refinement of the theoretical framework of immunology. In particular, natural killer cells and macrophages are activated by transient modifications, but adapt to long-lasting modifications that occur in the surrounding tissue environment. This process facilitates the maintenance of self-tolerance while permitting efficient immune responses. In this Essay we extend this idea to other components of the immune system and we propose some general principles that lay the foundations for a unifying theory of immunity — the discontinuity theory. According to this theoretical framework, effector immune responses (namely, activated responses that lead to the potential elimination of the target antigen) are induced by an antigenic discontinuity; that is, by the sudden modification of molecular motifs with which immune cells interact.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Natural killer cell tuning.
Figure 2: The induction of an immune response according to the discontinuity theory.

References

  1. Craver, C. F. in Blackwell Guide to the Philosophy of Science (eds Machamer, P. K. and Silberstein, M.), 55–79 (Blackwell, 2001).

    Google Scholar 

  2. Greenspan, N. S. Conceptualizing immune responsiveness. Nature Immunol. 8, 5–7 (2007).

    Article  CAS  Google Scholar 

  3. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    Article  CAS  Google Scholar 

  4. Orr, M. T. & Lanier, L. L. Natural killer cell education and tolerance. Cell 142, 847–856 (2010).

    Article  CAS  Google Scholar 

  5. Gasser, S. & Raulet, D. H. Activation and self-tolerance of natural killer cells. Immunol. Rev. 214, 130–142 (2006).

    Article  CAS  Google Scholar 

  6. Kärre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678 (1986).

    Article  Google Scholar 

  7. Höglund, P. et al. Recognition of β2-microglobulin-negative (β2m-) T-cell blasts by natural killer cells from normal but not from β2m- mice: nonresponsiveness controlled by β2m- bone marrow in chimeric mice. Proc. Natl Acad. Sci. USA 88, 10332–10336 (1991).

    Article  Google Scholar 

  8. Liao, N. S., Bix, M., Zijlstra, M., Jaenisch, R. & Raulet, D. MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253, 199–202 (1991).

    Article  CAS  Google Scholar 

  9. Joncker, N. T., Shifrin, N., Delebecque, F. & Raulet, D. H. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J. Exp. Med. 207, 2065–2072 (2010).

    Article  CAS  Google Scholar 

  10. Elliott, J. M., Wahle, J. A. & Yokoyama, W. M. MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J. Exp. Med. 207, 2073–2079 (2010).

    Article  CAS  Google Scholar 

  11. Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Rev. Immunol. 2, 965–975 (2002).

    Article  CAS  Google Scholar 

  12. Stuart, L. M. & Ezekowitz, R. A. Phagocytosis and comparative innate immunity: learning on the fly. Nature Rev. Immunol. 8, 131–141 (2008).

    Article  CAS  Google Scholar 

  13. Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nature Rev. Immunol. 9, 353–363 (2009).

    Article  CAS  Google Scholar 

  14. Jeannin, P., Jaillon, S. & Delneste, Y. Pattern recognition receptors in the immune response against dying cells. Curr. Opin. Immunol. 20, 530–537 (2008).

    Article  CAS  Google Scholar 

  15. Ahrens, S. et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36, 635–645 (2012).

    Article  CAS  Google Scholar 

  16. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  Google Scholar 

  17. Wang, H. et al. Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells. Proc. Natl Acad. Sci. USA 104, 13744–13749 (2007).

    Article  CAS  Google Scholar 

  18. Ramsdell, F. & Fowlkes, B. J. Maintenance of in vivo tolerance by persistence of antigen. Science 257, 1130–1134 (1992).

    Article  CAS  Google Scholar 

  19. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    Article  CAS  Google Scholar 

  20. Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).

    Article  CAS  Google Scholar 

  21. Utzschneider, D. T. et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nature Immunol. 14, 603–610 (2013).

    Article  CAS  Google Scholar 

  22. Turchinovich, G. & Hayday, A. C. Skint-1 identifies a common molecular mechanism for the development of interferon-γ-secreting versus interleukin-17-secreting γδ T cells. Immunity 35, 59–68 (2011).

    Article  CAS  Google Scholar 

  23. Grossman, Z. & Paul, W. E. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc. Natl Acad. Sci. USA 89, 10365–10369 (1992).

    Article  CAS  Google Scholar 

  24. Grossman, Z., Min, B., Meier-Schellersheim, M. & Paul, W. E. Concomitant regulation of T-cell activation and homeostasis. Nature Rev. Immunol. 4, 387–395 (2004).

    Article  CAS  Google Scholar 

  25. Schenten, D. & Medzhitov, R. The control of adaptive immune responses by the innate immune system. Adv. Immunol. 109, 87–124 (2011).

    Article  CAS  Google Scholar 

  26. Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    Article  CAS  Google Scholar 

  27. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    Article  CAS  Google Scholar 

  28. Smyth, M. J., Dunn, G. P. & Schreiber, R. D. in Advances in Immunology (ed. Allison, J. P.) 1–50 (Elsevier, 2006).

    Google Scholar 

  29. Raulet, D. H. & Guerra, N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors, Nature Rev. Immunol. 9, 568–580 (2009).

    Article  CAS  Google Scholar 

  30. Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330, 827–830 (2010).

    Article  CAS  Google Scholar 

  31. Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839 (2003).

    Article  CAS  Google Scholar 

  32. den Boer, A. T. et al. The tumoricidal activity of memory CD8+ T cells is hampered by persistent systemic antigen, but full functional capacity is regained in an antigen-free environment. J. Immunol. 172, 6074–6079 (2004).

    Article  CAS  Google Scholar 

  33. Drake, C. G., Jaffee, E. & Pardoll, D. M. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).

    Article  CAS  Google Scholar 

  34. Pradeu, T. & Carosella, E. D. On the definition of a criterion of immunogenicity. Proc. Natl Acad. Sci. USA 103, 17858–17861 (2006).

    Article  CAS  Google Scholar 

  35. Burnet, F. M. Cancer: a biological approach. Br. Med. J. 1, 1–7 (1957).

    Article  Google Scholar 

  36. Thomas, L. in Cellular and humoral aspects of the hypersensitive states (Lawrence, 1959).

    Google Scholar 

  37. Burnet, F. M. Immunological surveillance (Pergamon, 1970).

    Google Scholar 

  38. Zinkernagel, R. M. & Doherty, P. C. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytes choriomeningitis. Nature 251, 547–548 (1974).

    Article  CAS  Google Scholar 

  39. Houghton, A. N. Cancer antigens: immune recognition of self and altered self. J. Exp. Med. 180, 1–4 (1994).

    Article  CAS  Google Scholar 

  40. Laughlin, S. B. The role of sensory adaptation in the retina. J. Exp. Biol. 146, 39–62 (1989).

    CAS  PubMed  Google Scholar 

  41. Wark, B., Lundstrom, B. N. & Fairhall, A. Sensory adaptation. Curr. Opin. Neurobiol. 17, 423–429 (2007).

    Article  CAS  Google Scholar 

  42. Bray, D., Levin, M. D. & Morton-Firth, C. J. Receptor clustering as a cellular mechanism to control sensitivity. Nature 393, 85–88 (1998).

    Article  CAS  Google Scholar 

  43. Henrickson, S. E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nature Immunol. 9, 282–291 (2008).

    Article  CAS  Google Scholar 

  44. Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    Article  CAS  Google Scholar 

  45. Kyes, S., Horrocks, P. & Newbold, C. Antigenic variation at the infected red cell surface in malaria. Annu. Rev. Microbiol. 55, 673–707 (2001).

    Article  CAS  Google Scholar 

  46. MacGregor, P., Szöor, B., Savill, N. J. & Matthews, K. R. Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act. Nature Rev. Micro 10, 431–438 (2012).

    Article  CAS  Google Scholar 

  47. Ndung'u, T. & Weiss, R. A. On HIV diversity. AIDS 26, 1255–1260 (2012).

    Article  CAS  Google Scholar 

  48. Csikász-Nagy, A. & Soyer, O. S. Adaptive dynamics with a single two-state protein. J. R. Soc. Interface 5, S41–S47 (2008).

    Article  Google Scholar 

  49. Daëron, M., Jaeger, S., Du Pasquier, L. & Vivier, E. Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol. Rev. 224, 11–43 (2008).

    Article  Google Scholar 

  50. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  Google Scholar 

  51. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  52. Khattri, R., Cox, T., Yasayko, S.-A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  53. Kuhn, T. S. The structure of scientific revolutions (Univ. of Chicago Press, 1962).

    Google Scholar 

  54. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  Google Scholar 

  55. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  CAS  Google Scholar 

  56. Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

    Article  CAS  Google Scholar 

  57. Belkaid, Y. & Oldenhove, G. Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 29, 362–371 (2008).

    Article  CAS  Google Scholar 

  58. Shklovskaya, E. et al. Langerhans cells are precommitted to immune tolerance induction. Proc. Natl Acad. Sci. USA 108, 18049–18054 (2011).

    Article  CAS  Google Scholar 

  59. Carrat, F. & Flahault, A. Influenza vaccine: The challenge of antigenic drift. Vaccine 25, 6852–6862 (2007).

    Article  CAS  Google Scholar 

  60. Pradeu, T. The limits of the self: immunology and biological identity 131–183 (Oxford Univ. Press, 2012).

    Book  Google Scholar 

  61. Du Pasquier, L. & Bernard, C. C. A. Active suppression of the allogeneic histocompatibility reactions during the metamorphosis of the clawed toad Xenopus. Differentiation 16, 131–183 (1980).

    Article  Google Scholar 

  62. Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nature Med. 19, 465–472 (2013).

    Article  CAS  Google Scholar 

  63. Burks, A. W. et al. Oral immunotherapy for treatment of egg allergy in children. N. Engl. J. Med. 367, 233–243 (2012).

    Article  CAS  Google Scholar 

  64. Bernard, C. Experimental medicine. (original text published in 1865). (Transaction, 1999).

    Google Scholar 

  65. Popper, K. R. Logik der forschung: zur erkenntnistheorie der modernen naturwissenschaft. (J. Springer, 1935).

    Book  Google Scholar 

  66. National Research Council. The role of theory in advancing 21st-century biology: catalyzing transformative research. [online], (The National Academies, 2008).

  67. Guia, S. et al. Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance. Sci. Signal. 4, ra21 (2011).

    Article  Google Scholar 

Download references

Acknowledgements

We thank H. Brailly, L. Du Pasquier, J. Ewbank, M. Fougereau, P. Kourilsky, L. Périé, B. Malissen and A. Trautmann for their constructive comments, S. Guia and S. Ugolini for their experimental data on calcium flux, and C. Chapple for his editorial help. E.V.'s laboratory is supported by the European Research Council (THINK Advanced Grant) and by institutional grants from Institut National de la Santé et de la Recherche Médicale, Le Centre national de la recherche scientifique and Aix Marseille to Centre d'Immunologie de Marseille-Luminy. T.P. and E.V. are scholars of the Institut Universitaire de France.

Author information

Authors and Affiliations

  1. Philosophy Department, Université Paris-Sorbonne, 1 rue Victor Cousin, Paris, 75005, France

    Thomas Pradeu

  2. Centre d'Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, UM2, Campus de Luminy, Marseille, 13288, France

    Sébastien Jaeger

  3. INSERM, U 1104, Marseille, 13288, France

    Sébastien Jaeger

  4. Centre national de la recherche scientifique, UMR7280, Marseille, 13288, France

    Sébastien Jaeger

  5. Centre d'Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, UM2, Campus de Luminy, Marseille, 13288, France

    Eric Vivier

  6. INSERM, U 1104, Marseille, 13288, France

    Eric Vivier

  7. Centre national de la recherche scientifique, UMR7280, Marseille, 13288, France

    Eric Vivier

  8. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Conception, Marseille, 13385, France

    Eric Vivier

Authors
  1. Thomas Pradeu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sébastien Jaeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Vivier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Thomas Pradeu or Eric Vivier.

Ethics declarations

Competing interests

E.V. is cofounder and shareholder of Innate Pharma, Marseille, France. The other authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity?. Nat Rev Immunol 13, 764–769 (2013). https://doi.org/10.1038/nri3521

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3521

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