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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Aug 20;93(17):9102–9107. doi: 10.1073/pnas.93.17.9102

Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function.

T Zal 1, S Weiss 1, A Mellor 1, B Stockinger 1
PMCID: PMC38602  PMID: 8799161

Abstract

Allelic exclusion at the T-cell receptor alpha chain locus is incomplete resulting in the generation of T cells that express two T-cell receptors. The potential involvement of such T cells in autoimmunity has been suggested [Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M. & Lanzavecchia, A. (1993) Science 262, 422-424; Heath, W. R. & Miller, J. F. A. P. (1993) J. Exp. Med. 178, 1807-1811]. Here we show that expression of a second T-cell receptor can rescue T cells with autospecific receptors from thymic deletion and allow their exit into the periphery. Dual receptor T cells, created by constitutive expression of two transgenic T-cell receptors on a Rag1-/- background, are tolerant to self by maintaining low levels of autospecific receptor, but selfreactive effector function (killing) can be induced through activation via the second receptor. This opens the possibility that T cells carrying two receptors in the periphery of normal individuals contain putatively autoreactive cells that could engage in autoimmune effector functions after recognition of an unrelated environmental antigen.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arden B., Clark S. P., Kabelitz D., Mak T. W. Mouse T-cell receptor variable gene segment families. Immunogenetics. 1995;42(6):501–530. doi: 10.1007/BF00172177. [DOI] [PubMed] [Google Scholar]
  2. Bogen B., Dembic Z., Weiss S. Clonal deletion of specific thymocytes by an immunoglobulin idiotype. EMBO J. 1993 Jan;12(1):357–363. doi: 10.1002/j.1460-2075.1993.tb05664.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borgulya P., Kishi H., Uematsu Y., von Boehmer H. Exclusion and inclusion of alpha and beta T cell receptor alleles. Cell. 1992 May 1;69(3):529–537. doi: 10.1016/0092-8674(92)90453-j. [DOI] [PubMed] [Google Scholar]
  4. Cobbold S. P., Jayasuriya A., Nash A., Prospero T. D., Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature. 1984 Dec 6;312(5994):548–551. doi: 10.1038/312548a0. [DOI] [PubMed] [Google Scholar]
  5. Couez D., Malissen M., Buferne M., Schmitt-Verhulst A. M., Malissen B. Each of the two productive T cell receptor alpha-gene rearrangements found in both the A10 and BM 3.3 T cell clones give rise to an alpha chain which can contribute to the constitution of a surface-expressed alpha beta dimer. Int Immunol. 1991 Jul;3(7):719–729. doi: 10.1093/intimm/3.7.719. [DOI] [PubMed] [Google Scholar]
  6. Elliott J. I., Altmann D. M. Dual T cell receptor alpha chain T cells in autoimmunity. J Exp Med. 1995 Oct 1;182(4):953–959. doi: 10.1084/jem.182.4.953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Förster I., Hirose R., Arbeit J. M., Clausen B. E., Hanahan D. Limited capacity for tolerization of CD4+ T cells specific for a pancreatic beta cell neo-antigen. Immunity. 1995 Jun;2(6):573–585. doi: 10.1016/1074-7613(95)90002-0. [DOI] [PubMed] [Google Scholar]
  8. Goverman J., Woods A., Larson L., Weiner L. P., Hood L., Zaller D. M. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell. 1993 Feb 26;72(4):551–560. doi: 10.1016/0092-8674(93)90074-z. [DOI] [PubMed] [Google Scholar]
  9. Hardardottir F., Baron J. L., Janeway C. A., Jr T cells with two functional antigen-specific receptors. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):354–358. doi: 10.1073/pnas.92.2.354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Heath W. R., Carbone F. R., Bertolino P., Kelly J., Cose S., Miller J. F. Expression of two T cell receptor alpha chains on the surface of normal murine T cells. Eur J Immunol. 1995 Jun;25(6):1617–1623. doi: 10.1002/eji.1830250622. [DOI] [PubMed] [Google Scholar]
  11. Heath W. R., Miller J. F. Expression of two alpha chains on the surface of T cells in T cell receptor transgenic mice. J Exp Med. 1993 Nov 1;178(5):1807–1811. doi: 10.1084/jem.178.5.1807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hämmerling G. J., Schönrich G., Ferber I., Arnold B. Peripheral tolerance as a multi-step mechanism. Immunol Rev. 1993 Jun;133:93–104. doi: 10.1111/j.1600-065x.1993.tb01511.x. [DOI] [PubMed] [Google Scholar]
  13. Katz J. D., Wang B., Haskins K., Benoist C., Mathis D. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993 Sep 24;74(6):1089–1100. doi: 10.1016/0092-8674(93)90730-e. [DOI] [PubMed] [Google Scholar]
  14. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  15. Lafaille J. J., Nagashima K., Katsuki M., Tonegawa S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell. 1994 Aug 12;78(3):399–408. doi: 10.1016/0092-8674(94)90419-7. [DOI] [PubMed] [Google Scholar]
  16. Mason D. Allelic exclusion of alpha chains in TCRs. Int Immunol. 1994 Jun;6(6):881–885. doi: 10.1093/intimm/6.6.881. [DOI] [PubMed] [Google Scholar]
  17. Matzinger P. The JAM test. A simple assay for DNA fragmentation and cell death. J Immunol Methods. 1991 Dec 15;145(1-2):185–192. doi: 10.1016/0022-1759(91)90325-a. [DOI] [PubMed] [Google Scholar]
  18. Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
  19. Oldstone M. B. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. doi: 10.1016/0092-8674(87)90507-1. [DOI] [PubMed] [Google Scholar]
  20. Oldstone M. B., Nerenberg M., Southern P., Price J., Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell. 1991 Apr 19;65(2):319–331. doi: 10.1016/0092-8674(91)90165-u. [DOI] [PubMed] [Google Scholar]
  21. Padovan E., Casorati G., Dellabona P., Meyer S., Brockhaus M., Lanzavecchia A. Expression of two T cell receptor alpha chains: dual receptor T cells. Science. 1993 Oct 15;262(5132):422–424. doi: 10.1126/science.8211163. [DOI] [PubMed] [Google Scholar]
  22. Pircher H., Bürki K., Lang R., Hengartner H., Zinkernagel R. M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989 Nov 30;342(6249):559–561. doi: 10.1038/342559a0. [DOI] [PubMed] [Google Scholar]
  23. Pircher H., Rebaï N., Groettrup M., Grégoire C., Speiser D. E., Happ M. P., Palmer E., Zinkernagel R. M., Hengartner H., Malissen B. Preferential positive selection of V alpha 2+ CD8+ T cells in mouse strains expressing both H-2k and T cell receptor V alpha a haplotypes: determination with a V alpha 2-specific monoclonal antibody. Eur J Immunol. 1992 Feb;22(2):399–404. doi: 10.1002/eji.1830220217. [DOI] [PubMed] [Google Scholar]
  24. Röcken M., Urban J. F., Shevach E. M. Infection breaks T-cell tolerance. Nature. 1992 Sep 3;359(6390):79–82. doi: 10.1038/359079a0. [DOI] [PubMed] [Google Scholar]
  25. Schönrich G., Kalinke U., Momburg F., Malissen M., Schmitt-Verhulst A. M., Malissen B., Hämmerling G. J., Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. doi: 10.1016/0092-8674(91)90163-s. [DOI] [PubMed] [Google Scholar]
  26. Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature. 1988 Nov 3;336(6194):73–76. doi: 10.1038/336073a0. [DOI] [PubMed] [Google Scholar]
  27. Simpson E., Chandler P., Sponaas A., Millrain M., Dyson P. J. T cells with dual antigen specificity in T cell receptor transgenic mice rejecting allografts. Eur J Immunol. 1995 Oct;25(10):2813–2817. doi: 10.1002/eji.1830251015. [DOI] [PubMed] [Google Scholar]
  28. Sinha A. A., Lopez M. T., McDevitt H. O. Autoimmune diseases: the failure of self tolerance. Science. 1990 Jun 15;248(4961):1380–1388. doi: 10.1126/science.1972595. [DOI] [PubMed] [Google Scholar]
  29. Sponaas A. M., Tomlinson P. D., Antoniou J., Auphan N., Langlet C., Malissen B., Schmitt-Verhulst A. M., Mellor A. L. Induction of tolerance to self MHC class I molecules expressed under the control of milk protein or beta-globin gene promoters. Int Immunol. 1994 Feb;6(2):277–287. doi: 10.1093/intimm/6.2.277. [DOI] [PubMed] [Google Scholar]
  30. Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
  31. Stockinger B., Hausmann B. Functional recognition of in vivo processed self antigen. Int Immunol. 1994 Feb;6(2):247–254. doi: 10.1093/intimm/6.2.247. [DOI] [PubMed] [Google Scholar]
  32. Stockinger B., Zal T., Zal A., Gray D. B cells solicit their own help from T cells. J Exp Med. 1996 Mar 1;183(3):891–899. doi: 10.1084/jem.183.3.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zal T., Volkmann A., Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med. 1994 Dec 1;180(6):2089–2099. doi: 10.1084/jem.180.6.2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. von Boehmer H., Kisielow P. Self-nonself discrimination by T cells. Science. 1990 Jun 15;248(4961):1369–1373. doi: 10.1126/science.1972594. [DOI] [PubMed] [Google Scholar]

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