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.

  • Letter
  • Published:

Tolerance of class I histocompatibility antigens expressed extrathymically

Abstract

ALTHOUGH convincing evidence has been obtained for the imposition of self-tolerance by the intrathymic deletion of self-reactive T cells1–4, the development of tolerance to antigens which are expressed only in the periphery is not so well understood. We have approached this question by creating transgenic mice5 which carry a class I major histocompatibility complex (MHC) gene (H-2Kb) linked to the rat insulin promoter6. Mice expressing the transgene develop diabetes, but do not appear to mount an immune response against the transgene-expressing pancreaticβ-cells, even when the transgene is allogeneic with respect to the endogenous host H-2 antigens6. We have now explored the mechanism of this tolerance further. We find that spleen cells from pre-diabetic transgenic (RIP-Kb) mice do not kill targets bearing H-2Kb, whereas thymus cells from the same mice do. The unresponsiveness of these spleen cells can be reversed in vitro by providing recombinant interleukin-2 (rIL-2). In older, diabetic mice, responsiveness develops as the pancreatic β-cells are lost. Our results point to an extrathymic mechanism of tolerance induction, dependent on the continuous presence of antigen and the lack of IL-2 in the local environment of potentially reactive T cells.

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

Similar content being viewed by others

References

  1. Kappler, J. W., Roehm, N. & Marrack, P. Cell 49, 273–280 (1987).

    Article  CAS  Google Scholar 

  2. Kisielow, P., Blüthmann, Staerz, U. D., Steinmetz, M. & von Boehmer, H. Nature 333, 742–746 (1988).

    Article  ADS  CAS  Google Scholar 

  3. Sha, W. C. et al. Nature 336, 73–76 (1988).

    Article  ADS  CAS  Google Scholar 

  4. Sprent, J. & Webb, S. R. Adv. Immun 41, 39–133 (1987).

    Article  CAS  Google Scholar 

  5. Miller, J. F. A. P., Morahan, G. & Allison, J. Immun. Today 10, 53–57 (1989).

    Article  CAS  Google Scholar 

  6. Allison, J. et al. Nature 333, 529–533 (1988).

    Article  ADS  CAS  Google Scholar 

  7. Morahan, G. et al. Proc. natn. Acad. Sci. U.S.A. 86, 3782–3786 (1989).

    Article  ADS  CAS  Google Scholar 

  8. Kelso, A., Gough, N. & Metcalf, D. in Lymphokines in the Immune Response, (ed. Cohen, S.) (CRC, in the press).

  9. Essery, G., Feldman, M. & Lamb, J. R. Immunology 64, 413–417 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lo, D. et al. Cell 53, 159–168 (1988).

    Article  CAS  Google Scholar 

  11. Markmann, J., Lo, D., Naji, A., Palmiter, R. D., Brinster, R. L. & Heber-Katz, E. Nature 366, 476–479 (1988).

    Article  ADS  Google Scholar 

  12. Braciale, T. J. et al. Immunol. Rev. 98, 95–114 (1987).

    Article  CAS  Google Scholar 

  13. Arnold, B. et al. Proc. natn. Acad. Sci. U.S.A. 85, 2269–2273 (1988).

    Article  ADS  CAS  Google Scholar 

  14. Singer, A., Munitz, T. I., Golding, H., Rosenberg, A. S. & Mizuochi, T. Immunol. Rev. 98, 143–170 (1987).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morahan, G., Allison, J. & Miller, J. Tolerance of class I histocompatibility antigens expressed extrathymically. Nature 339, 622–624 (1989). https://doi.org/10.1038/339622a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/339622a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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