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. 1993 May 15;90(10):4409–4413. doi: 10.1073/pnas.90.10.4409

Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide.

J H Russell 1, B Rush 1, C Weaver 1, R Wang 1
PMCID: PMC46520  PMID: 8506280

Abstract

Antigen receptor-stimulated cell death of developing, immature T cells plays an important role in shaping the repertoire of antigens to which mature T cells will respond, but a role for receptor-stimulated death in controlling responses of mature T cells is controversial. Mutant lpr/lpr mice exhibit an autoimmune syndrome similar to systemic lupus erythematosus. Here we demonstrate that these mice have a defect in antigen-stimulated suicide of activated T cells in mature CD4+ and CD8+ T cell compartments. The defective suicide pathway is evident when the T cells are stimulated with antigen on antigen-presenting cells or with immobilized anti-CD3 in the absence of antigen-presenting cells. These studies, in concert with the work of others, suggest that antigen-stimulated death of mature cells may be important both in establishing peripheral tolerance and in limiting inflammation during normal immune responses.

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Selected References

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

  1. Cohen P. L., Eisenberg R. A. The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane. Immunol Today. 1992 Nov;13(11):427–428. doi: 10.1016/0167-5699(92)90066-G. [DOI] [PubMed] [Google Scholar]
  2. Cowan W. M., Fawcett J. W., O'Leary D. D., Stanfield B. B. Regressive events in neurogenesis. Science. 1984 Sep 21;225(4668):1258–1265. doi: 10.1126/science.6474175. [DOI] [PubMed] [Google Scholar]
  3. Freeman G. J., Gray G. S., Gimmi C. D., Lombard D. B., Zhou L. J., White M., Fingeroth J. D., Gribben J. G., Nadler L. M. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med. 1991 Sep 1;174(3):625–631. doi: 10.1084/jem.174.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Giese T., Davidson W. F. Evidence for early onset, polyclonal activation of T cell subsets in mice homozygous for lpr. J Immunol. 1992 Nov 1;149(9):3097–3106. [PubMed] [Google Scholar]
  5. Giese T., Davidson W. F. Evidence for early onset, polyclonal activation of T cell subsets in mice homozygous for lpr. J Immunol. 1992 Nov 1;149(9):3097–3106. [PubMed] [Google Scholar]
  6. Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
  7. Hsieh C. S., Heimberger A. B., Gold J. S., O'Garra A., Murphy K. M. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6065–6069. doi: 10.1073/pnas.89.13.6065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Janssen O., Wesselborg S., Heckl-Ostreicher B., Pechhold K., Bender A., Schondelmaier S., Moldenhauer G., Kabelitz D. T cell receptor/CD3-signaling induces death by apoptosis in human T cell receptor gamma delta + T cells. J Immunol. 1991 Jan 1;146(1):35–39. [PubMed] [Google Scholar]
  9. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  10. Kappler J. W., Staerz U., White J., Marrack P. C. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
  11. Kawabe Y., Ochi A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature. 1991 Jan 17;349(6306):245–248. doi: 10.1038/349245a0. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Kotzin B. L., Babcock S. K., Herron L. R. Deletion of potentially self-reactive T cell receptor specificities in L3T4-, Lyt-2- T cells of lpr mice. J Exp Med. 1988 Dec 1;168(6):2221–2229. doi: 10.1084/jem.168.6.2221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lenardo M. J. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. doi: 10.1038/353858a0. [DOI] [PubMed] [Google Scholar]
  15. Liu Y., Janeway C. A., Jr Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance. J Exp Med. 1990 Dec 1;172(6):1735–1739. doi: 10.1084/jem.172.6.1735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. MacDonald H. R., Baschieri S., Lees R. K. Clonal expansion precedes anergy and death of V beta 8+ peripheral T cells responding to staphylococcal enterotoxin B in vivo. Eur J Immunol. 1991 Aug;21(8):1963–1966. doi: 10.1002/eji.1830210827. [DOI] [PubMed] [Google Scholar]
  17. MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
  18. Matsumoto K., Yoshikai Y., Asano T., Himeno K., Iwasaki A., Nomoto K. Defect in negative selection in lpr donor-derived T cells differentiating in non-lpr host thymus. J Exp Med. 1991 Jan 1;173(1):127–136. doi: 10.1084/jem.173.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  20. Murphy K. M., Heimberger A. B., Loh D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. doi: 10.1126/science.2125367. [DOI] [PubMed] [Google Scholar]
  21. Oehm A., Behrmann I., Falk W., Pawlita M., Maier G., Klas C., Li-Weber M., Richards S., Dhein J., Trauth B. C. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem. 1992 May 25;267(15):10709–10715. [PubMed] [Google Scholar]
  22. Raveche E. S., Steinberg A. D., DeFranco A. L., Tjio J. H. Cell cycle analysis of lymphocyte activation in normal and autoimmune strains of mice. J Immunol. 1982 Sep;129(3):1219–1226. [PubMed] [Google Scholar]
  23. Rocha B., von Boehmer H. Peripheral selection of the T cell repertoire. Science. 1991 Mar 8;251(4998):1225–1228. doi: 10.1126/science.1900951. [DOI] [PubMed] [Google Scholar]
  24. Russell J. H., Meleedy-Rey P., McCulley D. E., Sha W. C., Nelson C. A., Loh D. Y. Evidence for CD8-independent T cell maturation in transgenic mice. J Immunol. 1990 May 1;144(9):3318–3325. [PubMed] [Google Scholar]
  25. Russell J. H., Rush B. J., Abrams S. I., Wang R. Sensitivity of T cells to anti-CD3-stimulated suicide is independent of functional phenotype. Eur J Immunol. 1992 Jun;22(6):1655–1658. doi: 10.1002/eji.1830220648. [DOI] [PubMed] [Google Scholar]
  26. Russell J. H., White C. L., Loh D. Y., Meleedy-Rey P. Receptor-stimulated death pathway is opened by antigen in mature T cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2151–2155. doi: 10.1073/pnas.88.6.2151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Singer P. A., Balderas R. S., McEvilly R. J., Bobardt M., Theofilopoulos A. N. Tolerance-related V beta clonal deletions in normal CD4-8-, TCR-alpha/beta + and abnormal lpr and gld cell populations. J Exp Med. 1989 Dec 1;170(6):1869–1877. doi: 10.1084/jem.170.6.1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
  31. Trauth B. C., Klas C., Peters A. M., Matzku S., Möller P., Falk W., Debatin K. M., Krammer P. H. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989 Jul 21;245(4915):301–305. doi: 10.1126/science.2787530. [DOI] [PubMed] [Google Scholar]
  32. Van Houten N., Budd R. C. Accelerated programmed cell death of MRL-lpr/lpr T lymphocytes. J Immunol. 1992 Oct 1;149(7):2513–2517. [PubMed] [Google Scholar]
  33. Watanabe-Fukunaga R., Brannan C. I., Copeland N. G., Jenkins N. A., Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. doi: 10.1038/356314a0. [DOI] [PubMed] [Google Scholar]
  34. Wofsy D., Hardy R. R., Seaman W. E. The proliferating cells in autoimmune MRL/lpr mice lack L3T4, an antigen on "helper" T cells that is involved in the response to class II major histocompatibility antigens. J Immunol. 1984 Jun;132(6):2686–2689. [PubMed] [Google Scholar]
  35. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  36. Yonehara S., Ishii A., Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. doi: 10.1084/jem.169.5.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zhou T., Bluethmann H., Eldridge J., Brockhaus M., Berry K., Mountz J. D. Abnormal thymocyte development and production of autoreactive T cells in T cell receptor transgenic autoimmune mice. J Immunol. 1991 Jul 15;147(2):466–474. [PubMed] [Google Scholar]
  38. Zhou T., Bluethmann H., Zhang J., Edwards C. K., 3rd, Mountz J. D. Defective maintenance of T cell tolerance to a superantigen in MRL-lpr/lpr mice. J Exp Med. 1992 Oct 1;176(4):1063–1072. doi: 10.1084/jem.176.4.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]

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