Abstract
Acute viral infections induce immune deficiencies, as shown by unresponsiveness to mitogens and unrelated antigens. T lymphocytes isolated from mice acutely infected with lymphocytic choriomeningitis virus (LCMV) were found in this study to undergo activation-induced apoptosis upon signalling through the T-cell receptor (TcR)-CD3 complex. Kinetic studies demonstrated that this sensitivity to apoptosis directly correlated with the induction of immune deficiency, as measured by impaired proliferation in response to anti-CD3 antibody or to concanavalin A. Cell cycling in interleukin-2 (IL-2) alone stimulated proliferation of LCMV-induced T cells without inducing apoptosis, but preculturing of T cells from acutely infected mice in IL-2 accelerated apoptosis upon subsequent TcR-CD3 cross-linking. T lymphocytes isolated from mice after the acute infection were less responsive to IL-2, but those T cells, presumably memory T cells, responding to IL-2 were primed in each case to die a rapid apoptotic death upon TcR-CD3 cross-linking. These results indicate that virus infection-induced unresponsiveness to T-cell mitogens is due to apoptosis of the activated lymphocytes and suggest that the sensitization of memory cells by IL-2 induced during infection will cause them to die upon antigen recognition, thereby impairing specific responses to nonviral antigens.
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Selected References
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- Akbar A. N., Amlot P. L., Ivory K., Timms A., Janossy G. Inhibition of alloresponsive naive and memory T cells by CD7 and CD25 antibodies and by cyclosporine. Transplantation. 1990 Nov;50(5):823–829. doi: 10.1097/00007890-199011000-00016. [DOI] [PubMed] [Google Scholar]
- Akbar A. N., Salmon M., Janossy G. The synergy between naive and memory T cells during activation. Immunol Today. 1991 Jun;12(6):184–188. doi: 10.1016/0167-5699(91)90050-4. [DOI] [PubMed] [Google Scholar]
- Ashwell J. D., Cunningham R. E., Noguchi P. D., Hernandez D. Cell growth cycle block of T cell hybridomas upon activation with antigen. J Exp Med. 1987 Jan 1;165(1):173–194. doi: 10.1084/jem.165.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Biron C. A., Welsh R. M. Blastogenesis of natural killer cells during viral infection in vivo. J Immunol. 1982 Dec;129(6):2788–2795. [PubMed] [Google Scholar]
- Buckle A. M., Hogg N. Human memory T cells express intercellular adhesion molecule-1 which can be increased by interleukin 2 and interferon-gamma. Eur J Immunol. 1990 Feb;20(2):337–341. doi: 10.1002/eji.1830200216. [DOI] [PubMed] [Google Scholar]
- Carlow D. A., Teh S. J., van Oers N. S., Miller R. G., Teh H. S. Peripheral tolerance through clonal deletion of mature CD4-CD8+ T cells. Int Immunol. 1992 May;4(5):599–610. doi: 10.1093/intimm/4.5.599. [DOI] [PubMed] [Google Scholar]
- Cohen J. J., Duke R. C., Fadok V. A., Sellins K. S. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. doi: 10.1146/annurev.iy.10.040192.001411. [DOI] [PubMed] [Google Scholar]
- Dancescu M., Rubio-Trujillo M., Biron G., Bron D., Delespesse G., Sarfati M. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med. 1992 Nov 1;176(5):1319–1326. doi: 10.1084/jem.176.5.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Groux H., Torpier G., Monté D., Mouton Y., Capron A., Ameisen J. C. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. doi: 10.1084/jem.175.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hartley S. B., Cooke M. P., Fulcher D. A., Harris A. W., Cory S., Basten A., Goodnow C. C. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell. 1993 Feb 12;72(3):325–335. doi: 10.1016/0092-8674(93)90111-3. [DOI] [PubMed] [Google Scholar]
- Inaba K., Steinman R. M. Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release. J Exp Med. 1984 Dec 1;160(6):1717–1735. doi: 10.1084/jem.160.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jacobs R. P., Cole G. A. Lymphocytic choriomeningitis virus-induced immunosuppression: a virus-induced macrophage defect. J Immunol. 1976 Sep;117(3):1004–1009. [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]
- Jenkinson E. J., Kingston R., Smith C. A., Williams G. T., Owen J. J. Antigen-induced apoptosis in developing T cells: a mechanism for negative selection of the T cell receptor repertoire. Eur J Immunol. 1989 Nov;19(11):2175–2177. doi: 10.1002/eji.1830191132. [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]
- 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]
- Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu Y., Janeway C. A., Jr Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3845–3849. doi: 10.1073/pnas.89.9.3845. [DOI] [PMC free article] [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]
- Matzinger P., Guerder S. Does T-cell tolerance require a dedicated antigen-presenting cell? Nature. 1989 Mar 2;338(6210):74–76. doi: 10.1038/338074a0. [DOI] [PubMed] [Google Scholar]
- McFarland H. I., Nahill S. R., Maciaszek J. W., Welsh R. M. CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992 Aug 15;149(4):1326–1333. [PubMed] [Google Scholar]
- Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
- Mims C. A., Wainwright S. The immunodepressive action of lymphocytic choriomeningitis virus in mice. J Immunol. 1968 Oct;101(4):717–724. [PubMed] [Google Scholar]
- Murakami M., Tsubata T., Okamoto M., Shimizu A., Kumagai S., Imura H., Honjo T. Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature. 1992 May 7;357(6373):77–80. doi: 10.1038/357077a0. [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]
- Nau G. J., Moldwin R. L., Lancki D. W., Kim D. K., Fitch F. W. Inhibition of IL 2-driven proliferation of murine T lymphocyte clones by supraoptimal levels of immobilized anti-T cell receptor monoclonal antibody. J Immunol. 1987 Jul 1;139(1):114–122. [PubMed] [Google Scholar]
- Nemazee D. A., Bürki K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 1989 Feb 9;337(6207):562–566. doi: 10.1038/337562a0. [DOI] [PubMed] [Google Scholar]
- Newell M. K., Haughn L. J., Maroun C. R., Julius M. H. Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature. 1990 Sep 20;347(6290):286–289. doi: 10.1038/347286a0. [DOI] [PubMed] [Google Scholar]
- Rouse B. T., Horohov D. W. Immunosuppression in viral infections. Rev Infect Dis. 1986 Nov-Dec;8(6):850–873. doi: 10.1093/clinids/8.6.850. [DOI] [PMC free article] [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]
- Saron M. F., Colle J. H., Dautry-Varsat A., Truffa-Bachi P. Activated T lymphocytes from mice infected by lymphocytic choriomeningitis virus display high affinity IL-2 receptors but do not proliferate in response to IL-2. J Immunol. 1991 Dec 15;147(12):4333–4337. [PubMed] [Google Scholar]
- Saron M. F., Shidani B., Nahori M. A., Guillon J. C., Truffa-Bachi P. Lymphocytic choriomeningitis virus-induced immunodepression: inherent defect of B and T lymphocytes. J Virol. 1990 Sep;64(9):4076–4083. doi: 10.1128/jvi.64.9.4076-4083.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schreiber S. L., Crabtree G. R. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–142. doi: 10.1016/0167-5699(92)90111-J. [DOI] [PubMed] [Google Scholar]
- Shi Y. F., Sahai B. M., Green D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. doi: 10.1038/339625a0. [DOI] [PubMed] [Google Scholar]
- Shi Y., Glynn J. M., Guilbert L. J., Cotter T. G., Bissonnette R. P., Green D. R. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 1992 Jul 10;257(5067):212–214. doi: 10.1126/science.1378649. [DOI] [PubMed] [Google Scholar]
- Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
- Swat W., Ignatowicz L., Kisielow P. Detection of apoptosis of immature CD4+8+ thymocytes by flow cytometry. J Immunol Methods. 1991 Mar 1;137(1):79–87. doi: 10.1016/0022-1759(91)90396-w. [DOI] [PubMed] [Google Scholar]
- Swat W., Ignatowicz L., von Boehmer H., Kisielow P. Clonal deletion of immature CD4+8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature. 1991 May 9;351(6322):150–153. doi: 10.1038/351150a0. [DOI] [PubMed] [Google Scholar]
- Tabi Z., Lynch F., Ceredig R., Allan J. E., Doherty P. C. Virus-specific memory T cells are Pgp-1+ and can be selectively activated with phorbol ester and calcium ionophore. Cell Immunol. 1988 May;113(2):268–277. doi: 10.1016/0008-8749(88)90026-3. [DOI] [PubMed] [Google Scholar]
- Teh H. S., Kishi H., Scott B., Von Boehmer H. Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules. J Exp Med. 1989 Mar 1;169(3):795–806. doi: 10.1084/jem.169.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tony H. P., Parker D. C. Major histocompatibility complex-restricted, polyclonal B cell responses resulting from helper T cell recognition of antiimmunoglobulin presented by small B lymphocytes. J Exp Med. 1985 Jan 1;161(1):223–241. doi: 10.1084/jem.161.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ucker D. S., Meyers J., Obermiller P. S. Activation-driven T cell death. II. Quantitative differences alone distinguish stimuli triggering nontransformed T cell proliferation or death. J Immunol. 1992 Sep 1;149(5):1583–1592. [PubMed] [Google Scholar]
- Uehara T., Miyawaki T., Ohta K., Tamaru Y., Yokoi T., Nakamura S., Taniguchi N. Apoptotic cell death of primed CD45RO+ T lymphocytes in Epstein-Barr virus-induced infectious mononucleosis. Blood. 1992 Jul 15;80(2):452–458. [PubMed] [Google Scholar]
- Vitetta E. S., Berton M. T., Burger C., Kepron M., Lee W. T., Yin X. M. Memory B and T cells. Annu Rev Immunol. 1991;9:193–217. doi: 10.1146/annurev.iy.09.040191.001205. [DOI] [PubMed] [Google Scholar]
- Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
- Welsh R. M., Jr, Doe W. F. Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice: natural killer cell activity in cultured spleen leukocytes concomitant with T-cell-dependent immune interferon production. Infect Immun. 1980 Nov;30(2):473–483. doi: 10.1128/iai.30.2.473-483.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]