Abstract
Infection of mice with lymphocytic choriomeningitis virus (LCMV) causes a major expansion of CD8+ T cells followed by a period of immune downregulation that coincides with the induction of lymphocyte apoptosis in the mouse spleen. CD95 (Fas) and its ligand are important for regulating peripheral T-lymphocyte numbers and can mediate apoptosis of mature T lymphocytes. We infected CD95- and CD95L-deficient mice (lpr and gld, respectively) with LCMV to determine if the immune downregulation that occurred following resolution of the LCMV infection was due to a CD95-dependent apoptotic mechanism. Lymphocytes from LCMV-infected lpr and gld mice were capable of normal T-cell expansion and cytolytic function but were, in contrast to activated cells from normal virus-infected mice, relatively more resistant to T-cell receptor-induced apoptosis in vitro. However, in vivo there were significant numbers of apoptotic cells in the spleens of lpr and gld mice recovering from the infection, and the T-cell number and cytolytic activity decreased to normal postinfection levels. Thus, CD95 is not required for the immune downregulation of the CD8+-T-lymphocyte response following acute LCMV infection.
Full Text
The Full Text of this article is available as a PDF (184.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alderson M. R., Tough T. W., Davis-Smith T., Braddy S., Falk B., Schooley K. A., Goodwin R. G., Smith C. A., Ramsdell F., Lynch D. H. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71–77. doi: 10.1084/jem.181.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
- Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
- Drappa J., Brot N., Elkon K. B. The Fas protein is expressed at high levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10340–10344. doi: 10.1073/pnas.90.21.10340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Duke R. C., Cohen J. J. IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells. Lymphokine Res. 1986 Fall;5(4):289–299. [PubMed] [Google Scholar]
- Fisher G. H., Rosenberg F. J., Straus S. E., Dale J. K., Middleton L. A., Lin A. Y., Strober W., Lenardo M. J., Puck J. M. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995 Jun 16;81(6):935–946. doi: 10.1016/0092-8674(95)90013-6. [DOI] [PubMed] [Google Scholar]
- Gillette-Ferguson I., Sidman C. L. A specific intercellular pathway of apoptotic cell death is defective in the mature peripheral T cells of autoimmune lpr and gld mice. Eur J Immunol. 1994 May;24(5):1181–1185. doi: 10.1002/eji.1830240526. [DOI] [PubMed] [Google Scholar]
- Glickstein L. J., Huber B. T. Karoushi--death by overwork in the immune system. J Immunol. 1995 Jul 15;155(2):522–524. [PubMed] [Google Scholar]
- Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
- Kägi D., Seiler P., Pavlovic J., Ledermann B., Bürki K., Zinkernagel R. M., Hengartner H. The roles of perforin- and Fas-dependent cytotoxicity in protection against cytopathic and noncytopathic viruses. Eur J Immunol. 1995 Dec;25(12):3256–3262. doi: 10.1002/eji.1830251209. [DOI] [PubMed] [Google Scholar]
- Lau L. L., Jamieson B. D., Somasundaram T., Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994 Jun 23;369(6482):648–652. doi: 10.1038/369648a0. [DOI] [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]
- Lynch D. H., Ramsdell F., Alderson M. R. Fas and FasL in the homeostatic regulation of immune responses. Immunol Today. 1995 Dec;16(12):569–574. doi: 10.1016/0167-5699(95)80079-4. [DOI] [PubMed] [Google Scholar]
- Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
- Owen-Schaub L. B., Yonehara S., Crump W. L., 3rd, Grimm E. A. DNA fragmentation and cell death is selectively triggered in activated human lymphocytes by Fas antigen engagement. Cell Immunol. 1992 Mar;140(1):197–205. doi: 10.1016/0008-8749(92)90187-t. [DOI] [PubMed] [Google Scholar]
- Razvi E. S., Jiang Z., Woda B. A., Welsh R. M. Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice. Am J Pathol. 1995 Jul;147(1):79–91. [PMC free article] [PubMed] [Google Scholar]
- Razvi E. S., Welsh R. M., McFarland H. I. In vivo state of antiviral CTL precursors. Characterization of a cycling cell population containing CTL precursors in immune mice. J Immunol. 1995 Jan 15;154(2):620–632. [PubMed] [Google Scholar]
- Razvi E. S., Welsh R. M. Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus-induced immune deficiency. J Virol. 1993 Oct;67(10):5754–5765. doi: 10.1128/jvi.67.10.5754-5765.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rieux-Laucat F., Le Deist F., Hivroz C., Roberts I. A., Debatin K. M., Fischer A., de Villartay J. P. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995 Jun 2;268(5215):1347–1349. doi: 10.1126/science.7539157. [DOI] [PubMed] [Google Scholar]
- Russell J. H., Rush B., Weaver C., Wang R. Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4409–4413. doi: 10.1073/pnas.90.10.4409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Russell J. H., Wang R. Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells. Eur J Immunol. 1993 Sep;23(9):2379–2382. doi: 10.1002/eji.1830230951. [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]
- Selin L. K., Vergilis K., Welsh R. M., Nahill S. R. Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J Exp Med. 1996 Jun 1;183(6):2489–2499. doi: 10.1084/jem.183.6.2489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Selin L. K., Welsh R. M. Specificity and editing by apoptosis of virus-induced cytotoxic T lymphocytes. Curr Opin Immunol. 1994 Aug;6(4):553–559. doi: 10.1016/0952-7915(94)90140-6. [DOI] [PubMed] [Google Scholar]
- Singer G. G., Abbas A. K. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
- Strasser A. Apoptosis. Death of a T cell. Nature. 1995 Feb 2;373(6513):385–386. doi: 10.1038/373385a0. [DOI] [PubMed] [Google Scholar]
- Suda T., Takahashi T., Golstein P., Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993 Dec 17;75(6):1169–1178. doi: 10.1016/0092-8674(93)90326-l. [DOI] [PubMed] [Google Scholar]
- Takahashi T., Tanaka M., Brannan C. I., Jenkins N. A., Copeland N. G., Suda T., Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994 Mar 25;76(6):969–976. doi: 10.1016/0092-8674(94)90375-1. [DOI] [PubMed] [Google Scholar]
- Telford W. G., King L. E., Fraker P. J. Rapid quantitation of apoptosis in pure and heterogeneous cell populations using flow cytometry. J Immunol Methods. 1994 Jun 3;172(1):1–16. doi: 10.1016/0022-1759(94)90373-5. [DOI] [PubMed] [Google Scholar]
- Vignaux F., Vivier E., Malissen B., Depraetere V., Nagata S., Golstein P. TCR/CD3 coupling to Fas-based cytotoxicity. J Exp Med. 1995 Feb 1;181(2):781–786. doi: 10.1084/jem.181.2.781. [DOI] [PMC free article] [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]
- Yoshino T., Kondo E., Cao L., Takahashi K., Hayashi K., Nomura S., Akagi T. Inverse expression of bcl-2 protein and Fas antigen in lymphoblasts in peripheral lymph nodes and activated peripheral blood T and B lymphocytes. Blood. 1994 Apr 1;83(7):1856–1861. [PubMed] [Google Scholar]
- Zheng L., Fisher G., Miller R. E., Peschon J., Lynch D. H., Lenardo M. J. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995 Sep 28;377(6547):348–351. doi: 10.1038/377348a0. [DOI] [PubMed] [Google Scholar]