Skip to main content
Log in

Self-tolerance and the composition of T cell repertoire

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

T cell recognition of self-major histocompatibility complexpeptide complexes dictates the composition of the T cell receptor repertoire. Research projects in our laboratory deal with the mechanisms that regulate the composition of the repertoire specific for self-antigens and the defects that can result in autoimmunity. Two different types of disease models are under investigation: juvenile (type 1) diabetes and cancer. Both of these diseases are impacted by the presence of anti-self CD8 cells, yet in opposite ways. By understanding the mechanisms of peripheral tolerance and the reasons they fail in autoimmunity, we may learn how to prevent undersirable autoimmunity and how to encourage an autoimmune response when it is needed to eliminate tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Davis MM, Bjorkman PJ: T-cell antigen receptor genes and T-cell recognition. Nature 1988;334:395–402.

    Article  PubMed  CAS  Google Scholar 

  2. Zinkernagel RM, Doherty PC: Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 1974;248:701, 702.

    Article  PubMed  CAS  Google Scholar 

  3. Babbitt BP, Allen PM, Matsueda G, Haber E, Unanue RR: Binding of immunogenic peptides to Ia histocompatibility molecules. Nature 1985;317:359–361.

    Article  PubMed  CAS  Google Scholar 

  4. Townsend AR, Gotch FM, Davie J: Cytotoxic T cells recognize fragments of the influenza nucleoprotein. Cell 1985;42:457–467.

    Article  PubMed  CAS  Google Scholar 

  5. Jameson SC, Hogquist KA, Bevan MJ: Positive selection of thymocytes. Annu Rev Immunol 1995;13:93–126.

    Article  PubMed  CAS  Google Scholar 

  6. Kisielow P, von Boehmer H: Development and selection of T cells: facts and puzzles. Adv Immunol 1995;58:87–209.

    Article  PubMed  CAS  Google Scholar 

  7. Goldrath AW, Bevan M: Selecting and maintaining: a diverse T-cell repertoire. Nature 1999;402:255–262.

    Article  PubMed  CAS  Google Scholar 

  8. Lo D, Freedman J, Hesse SV, Palmiter RD, Brinster RL, Sherman LA: Peripheral tolerance to an islet cell specific hemagglutinin transgene affects both CD4+ and CD8+ T cells. Eur J Immunol 1992; 22:1013–1022.

    Article  PubMed  CAS  Google Scholar 

  9. Morgan DJ, Liblau R, Scott B, Fleck S, McDevitt H, Sarvetnick N, Lo D, Sherman LA: CD8+T cell mediated spontaneous diabetes in neonatal mice. J Immunol 1996;157:978–983.

    PubMed  CAS  Google Scholar 

  10. Morgan DJ, Kurts C, Kreuwel HCT, Holst KL, Heath WR, Sherman LA: Ontogeny of T cell tolerance to peripherally expressed antigens. Proc Natl Acad Sci 1999;96:3854–3858.

    Article  PubMed  CAS  Google Scholar 

  11. Morgan DJ, Kreuwel HCT, Sherman LA: Antigen concentration and precursorfrequency determine the rate of CD8+T cell tolerance to peripherally-expressed antigens. J Immunol 1999;163:723–727.

    PubMed  CAS  Google Scholar 

  12. Kurts C, Kosaka H, Carbone FR, Miller JFAP, Heath WR Class I-restricted cross-presentation of exogenous self antigens leads to deletion of autoreactive CD8+ T cells. J Exp Med 1997;186:239–245.

    Article  PubMed  CAS  Google Scholar 

  13. Morgan DJ, Kreuwel HCT, Fleck S, Levitsky HI, Pardoll DM, Sherman LA: Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity. J Immunol 1998; 160:643–651.

    PubMed  CAS  Google Scholar 

  14. Rocha B, von Boehmer H: Peripheral selection of the T cell repertoire. Science 1991;251:1225–1228.

    Article  PubMed  CAS  Google Scholar 

  15. Zhang L: The fate of adoptively transferrd antigen-specific T cells in vivo. Eur J Immunol 1996;26:2208–2214.

    Article  PubMed  CAS  Google Scholar 

  16. Schonrich G, Kalinke U, Momburg F, Malissen M, Schmitt-Verhulst AM, Malissen B, Hammerling GJ, Arnold B: Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 1991;65:293–304.

    Article  PubMed  CAS  Google Scholar 

  17. Padovan E, Casorali G, Dellatona P, Meyer S, Brockhaus M, Lanzavecchia A: Expression of two T cell receptor α chains: dual receptor T cells. Science 1993;262:422–424.

    Article  PubMed  CAS  Google Scholar 

  18. Heath WR, Carbone FR, Bertonlino P, Kelly J, Cose S, Miller JFAP: Expression of two T cell receptor α chains on the surface of normal murine T cells. Eur J Immunol 1995;25:1617–1623.

    Article  PubMed  CAS  Google Scholar 

  19. Blichfeld EML, Rotnes JS, Bogen B: Dual T cell receptor T cell have a decreased sensitivity to physiological ligands due to reduced density of each T cell receptor. Eur J Immunol 1996;26:2876–2884.

    Article  Google Scholar 

  20. Zal T, Weiss S, Mellor A, Stockinger B: Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. Proc Natl Acad Sci USA 1996;93:9102–9107.

    PubMed  CAS  Google Scholar 

  21. Sarukhan AC, Garcia C, Lanoue A, von Boehmer H: Allelic inclusion of T cell receptor a genes poses an autoimmune hazard due to low-level expression of autospecific receptors. Immunity 1998;8:563–570.

    Article  PubMed  CAS  Google Scholar 

  22. Hämmerling GJ, Schönrich G, Ferber I, Arnold B: Peripheral tolerance as a multi-step mechanism. Immunol Rev 1993;133:93–104.

    Article  PubMed  Google Scholar 

  23. Dillon SR, MacKay VL, Fink PJ: A functionally compromised intermediate in extrathymic CD8+ T cell deletion. Immunity 1995;3:321–333.

    Article  PubMed  CAS  Google Scholar 

  24. Rocha B, Grandien A, Freitas AA: Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance. J Exp Med 1995;181:993–1003.

    Article  PubMed  CAS  Google Scholar 

  25. Kawai K, Ohashi PS: Immunological function of a defined T-cell population to lerized to low-affinity self antigens. Nature 1995;374:68,69.

    Article  PubMed  CAS  Google Scholar 

  26. Rocha B, Tanchot C, von Boehmer H: Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen. J Exp Med 1993;177:1517–1521.

    Article  PubMed  CAS  Google Scholar 

  27. Dubois PM, Pihlgren M, Tomkowiak M, Mechenlen MV, Marvel J: Tolerant CD8 T cells induced by multiple injections of peptide antigen show impaired TCR signaling and altered proliferative responses in vitro and in vivo. J Immunol 1998;161:5260–5267.

    PubMed  CAS  Google Scholar 

  28. Nugent CT, Morgan DJ, Biggs J, Ko A, Pilip IM, Pamer EG, Sherman LA: Characterization of CD8+ T lymphocytes that persist after peripheral tolerance to a self antigen expressed in the pancreas. J Immunol, 2000;164:191–200.

    PubMed  CAS  Google Scholar 

  29. Wicker LS, Todd JA, Peterson LB: Genetic control of autoimmune diabetes in the NOD mouse. Annu Rev Immunol 1995;13:179–200.

    Article  PubMed  CAS  Google Scholar 

  30. Ridgway WM, Fasso M, Lanctot A, Garvey C, Fathman CG: Breaking self-tolerance in non-obesediabetic mice. J Exp Med 1996;183:1657–1662.

    Article  PubMed  CAS  Google Scholar 

  31. Geng L, Solimena M, Flavell FA, Sherwin RS, Hayday AC: Wide-spread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Proc Natl Acad Sci USA 1998;95:10,055–10,060.

    Article  CAS  Google Scholar 

  32. Nabavieh A, Chou H, Volokhov I, Lee JE, Purdy LE, Elliott JF, Singh B, Madrenas J: Development of an 1-Ag7 expressing antigen-presenting cell line: intrinsic molecular defect in compact 1-Ag7 dimer generation. J Autoimmunity 1998;11:63–71.

    Article  CAS  Google Scholar 

  33. Kanagawa O, Martins SM, Vaupel BA, Carrasco-Martin E, Unanue ER: Autorectivity of T cells from non-obese diabetic mice: an 1-Ag7-dependant reaction. Proc Natl Acad Sci USA 1998;95:1721–1724.

    Article  PubMed  CAS  Google Scholar 

  34. Salojin K, Zheng J, Cameron M, Gill B, Arreaza G, Ochi A.

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sherman, L.A., Morgan, D.J., Nugent, C.T. et al. Self-tolerance and the composition of T cell repertoire. Immunol Res 21, 305–313 (2000). https://doi.org/10.1385/IR:21:2-3:305

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/IR:21:2-3:305

Key Words

Navigation