Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
J Virol. 1993 Oct; 67(10): 5754–5765.
doi: 10.1128/jvi.67.10.5754-5765.1993
PMCID: PMC237993
PMID: 8371341

Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus-induced immune deficiency.

E S Razvi and R M Welsh
Author information Copyright and License information Disclaimer

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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

 
icon of scanned page 5754
5754
icon of scanned page 5755
5755
icon of scanned page 5756
5756
icon of scanned page 5757
5757
icon of scanned page 5758
5758
icon of scanned page 5759
5759
icon of scanned page 5760
5760
icon of scanned page 5761
5761
icon of scanned page 5762
5762
icon of scanned page 5763
5763
icon of scanned page 5764
5764
icon of scanned page 5765
5765
 

Images in this article

Image

Image
on p.5759

Click on the image to see a larger version.

Selected References

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

  • Akbar AN, Amlot PL, 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. [PubMed] [Google Scholar]
  • Akbar AN, Salmon M, Janossy G. The synergy between naive and memory T cells during activation. Immunol Today. 1991 Jun;12(6):184–188. [PubMed] [Google Scholar]
  • Ashwell JD, Cunningham RE, Noguchi PD, Hernandez D. Cell growth cycle block of T cell hybridomas upon activation with antigen. J Exp Med. 1987 Jan 1;165(1):173–194. [PMC free article] [PubMed] [Google Scholar]
  • Biron CA, Welsh RM. Blastogenesis of natural killer cells during viral infection in vivo. J Immunol. 1982 Dec;129(6):2788–2795. [PubMed] [Google Scholar]
  • Buckle AM, 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. [PubMed] [Google Scholar]
  • Carlow DA, Teh SJ, van Oers NS, Miller RG, Teh HS. Peripheral tolerance through clonal deletion of mature CD4-CD8+ T cells. Int Immunol. 1992 May;4(5):599–610. [PubMed] [Google Scholar]
  • Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. [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. [PMC free article] [PubMed] [Google Scholar]
  • Groux H, Torpier G, Monté D, Mouton Y, Capron A, Ameisen JC. 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. [PMC free article] [PubMed] [Google Scholar]
  • Hartley SB, Cooke MP, Fulcher DA, Harris AW, Cory S, Basten A, Goodnow CC. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell. 1993 Feb 12;72(3):325–335. [PubMed] [Google Scholar]
  • Inaba K, Steinman RM. 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. [PMC free article] [PubMed] [Google Scholar]
  • Jacobs RP, Cole GA. 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 EJ, Kingston R, Smith CA, Williams GT, Owen JJ. 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. [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. [PubMed] [Google Scholar]
  • Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. [PubMed] [Google Scholar]
  • Leo O, Foo M, Sachs DH, Samelson LE, Bluestone JA. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. [PMC free article] [PubMed] [Google Scholar]
  • Liu Y, Janeway CA., 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. [PMC free article] [PubMed] [Google Scholar]
  • Liu Y, Janeway CA., 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. [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. [PubMed] [Google Scholar]
  • McFarland HI, Nahill SR, Maciaszek JW, Welsh RM. 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 SA, Jonker RR, Mijnster MJ, Keet RP, Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. [PubMed] [Google Scholar]
  • Mims CA, 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. [PubMed] [Google Scholar]
  • Murphy KM, Heimberger AB, Loh DY. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. [PubMed] [Google Scholar]
  • Nau GJ, Moldwin RL, Lancki DW, Kim DK, Fitch FW. 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 DA, 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. [PubMed] [Google Scholar]
  • Newell MK, Haughn LJ, Maroun CR, Julius MH. 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. [PubMed] [Google Scholar]
  • Rouse BT, Horohov DW. Immunosuppression in viral infections. Rev Infect Dis. 1986 Nov-Dec;8(6):850–873. [PMC free article] [PubMed] [Google Scholar]
  • Russell JH, White CL, Loh DY, 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. [PMC free article] [PubMed] [Google Scholar]
  • Saron MF, Colle JH, 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 MF, Shidani B, Nahori MA, Guillon JC, Truffa-Bachi P. Lymphocytic choriomeningitis virus-induced immunodepression: inherent defect of B and T lymphocytes. J Virol. 1990 Sep;64(9):4076–4083. [PMC free article] [PubMed] [Google Scholar]
  • Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–142. [PubMed] [Google Scholar]
  • Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 1992 Jul 10;257(5067):212–214. [PubMed] [Google Scholar]
  • Shi YF, Sahai BM, Green DR. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. [PubMed] [Google Scholar]
  • Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. 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. [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. [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. [PubMed] [Google Scholar]
  • Tabi Z, Lynch F, Ceredig R, Allan JE, Doherty PC. 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. [PubMed] [Google Scholar]
  • Teh HS, 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. [PMC free article] [PubMed] [Google Scholar]
  • Tony HP, Parker DC. 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. [PMC free article] [PubMed] [Google Scholar]
  • Ucker DS, Meyers J, Obermiller PS. 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 ES, Berton MT, Burger C, Kepron M, Lee WT, Yin XM. Memory B and T cells. Annu Rev Immunol. 1991;9:193–217. [PubMed] [Google Scholar]
  • von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. [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. [PubMed] [Google Scholar]
  • Welsh RM, Jr, Doe WF. 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. [PMC free article] [PubMed] [Google Scholar]
Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)