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
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- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]