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.

  • Overview
  • Published:

Levees of immunological tolerance

Abstract

Immunological tolerance guards against spurious immune responses to body constituents. Tolerance encompasses a network of mechanisms: central and peripheral, cell-autonomous and cell-interactive. Our understanding of these mechanisms has improved greatly over recent years, often reflecting new insights into the processes underlying particular autoimmune diseases. Yet it is possible that important tolerance mechanisms remain to be discovered, perhaps an explanation for the so-far disappointing clinical translation to the prevention and cure of autoimmune diseases.

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

References

  1. von Boehmer, H. & Melchers, F. Checkpoints in lymphocyte development and autoimmune disease. Nat. Immunol. 11, 14–20 (2010).

    Article  CAS  Google Scholar 

  2. Mueller, D.L. The problem of peripheral self-peptide–MHC recognition: mechanisms maintaining peripheral tolerance. 11, 21–27 (2010).

  3. Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11, 7–13 (2010).

    Article  CAS  Google Scholar 

  4. Chen, Z., Benoist, C. & Mathis, D. How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc. Natl. Acad. Sci. USA 102, 14735–14740 (2005).

    Article  CAS  Google Scholar 

  5. Nagamine, K. et al. Positional cloning of the APECED gene. Nat. Genet. 17, 393–398 (1997).

    Article  CAS  Google Scholar 

  6. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17, 399–403 (1997).

  7. Klein, L., Klugmann, M., Nave, K.-A., Tuohy, V.K. & Kyewski, B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6, 56–61 (2000).

    Article  CAS  Google Scholar 

  8. Anderson, A.C. et al. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191, 761–770 (2000).

    Article  CAS  Google Scholar 

  9. Liu, G.Y. et al. Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3, 407–415 (1995).

    Article  CAS  Google Scholar 

  10. Anderton, S.M. Post-translational modifications of self antigens: implications for autoimmunity. Curr. Opin. Immunol. 16, 753–758 (2004).

    Article  CAS  Google Scholar 

  11. Gammon, G. & Sercarz, E. How some T cells escape tolerance induction. Nature 342, 183–185 (1989).

    Article  CAS  Google Scholar 

  12. Wucherpfennig, K.W., Call, M.J., Deng, L. & Mariuzza, R. Structural alterations in peptide-MHC recognition by self-reactive T cell receptors. Curr. Opin. Immunol. (published online, doi:10.1016/j.coi.2009.07.008 (19 August 2009).

  13. Mingueneau, M. et al. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 31, 197–208 (2009).

    Article  CAS  Google Scholar 

  14. Binstadt, B.A. et al. The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms. Proc. Natl. Acad. Sci. USA 106, 16758–16763 (2009).

    Article  CAS  Google Scholar 

  15. Wildin, R.S., Smyk-Pearson, S. & Filipovich, A.H. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet. 39, 537–545 (2002).

    Article  CAS  Google Scholar 

  16. Rasooly, L., Burek, C.L. & Rose, N.R. Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin. Immunol. Immunopathol. 81, 287–292 (1996).

    Article  CAS  Google Scholar 

  17. Vaysburd, M., Lock, C. & McDevitt, H. Prevention of insulin-dependent diabetes mellitus in nonobese diabetic mice by immunogenic but not by tolerated peptides. J. Exp. Med. 182, 897–902 (1995).

    Article  CAS  Google Scholar 

  18. Jiang, W., Anderson, M.S., Bronson, R., Mathis, D. & Benoist, C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 202, 805–815 (2005).

    Article  CAS  Google Scholar 

  19. Niki, S. et al. Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice. J. Clin. Invest. 116, 1292–1301 (2006).

    Article  CAS  Google Scholar 

  20. Meagher, C. et al. Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice. J. Immunol. 180, 7793–7803 (2008).

    Article  CAS  Google Scholar 

  21. Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).

    Article  CAS  Google Scholar 

  22. Chervonsky, A.V. Influence of microbial environment on autoimmunity. Nat. Immunol. 11, 28–35 (2010).

    Article  CAS  Google Scholar 

  23. Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    Article  Google Scholar 

  24. Martin, F. & Chan, A.C. B cell immunobiology in disease: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).

    Article  CAS  Google Scholar 

  25. Leandro, M.J. & de la Torre, I. Translational mini-review series on B cell-directed therapies: the pathogenic role of B cells in autoantibody-associated autoimmune diseases–lessons from B cell-depletion therapy. Clin. Exp. Immunol. 157, 191–197 (2009).

    Article  CAS  Google Scholar 

  26. Dorner, T., Radbruch, A. & Burmester, G.R. B-cell-directed therapies for autoimmune disease. Nat. Rev. Rheumatol. 5, 433–441 (2009).

    Article  Google Scholar 

  27. Steinman, L. Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat. Immunol. 11, 41–44 (2010).

    Article  CAS  Google Scholar 

  28. Palmer, M.T. & Weaver, C.T. Autoimmunity: increasing suspects in the CD4+ T cell lineup. 11, 36–40 (2010).

Download references

Acknowledgements

The authors' laboratory is funded by grants from the US National Institutes of Health (DK059658, DK060027, AI051530, AI56299) and the Juvenile Diabetes Research Foundation (4-2007-1057).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Diane Mathis or Christophe Benoist.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mathis, D., Benoist, C. Levees of immunological tolerance. Nat Immunol 11, 3–6 (2010). https://doi.org/10.1038/ni.1833

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1833

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