Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Am J Pathol. 1995 Jul; 147(1): 79–91.
PMCID: PMC1869886
PMID: 7604887

Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice.

E. S. Razvi, Z. Jiang, B. A. Woda, and R. M. Welsh
Author information Copyright and License information Disclaimer

Abstract

This report examines the mechanisms involved in the down-regulation of the immune response in acute viral infection and documents the presence of apoptotic lymphocytes in situ in the spleens of mice during the resolution of the immune response to acute lymphocytic choriomeningitis virus infection. Apoptotic cells were detected by an in situ nucleotidyl transferase assay. Both T and B lymphocytes were shown to be dying in vivo, the latter in clusters. A biphasic occurrence of apoptosis during the course of the acute infection was observed, with elevated levels occurring at day 3 after infection and a second more pronounced peak at day 11 after infection, coincident with the decline of the cytotoxic T lymphocyte response and with the decrease in total splenic leukocyte number. Apoptosis in vivo was detected in lpr mice, suggesting that Fas expression is not imperative for lymphocyte apoptosis in the context of an acute viral infection. Apoptosis in situ and the decline of the T lymphocyte response to acute lymphocytic choriomeningitis virus infection was unaffected by the enforced lymphocyte-directed expression of Bcl-2, a protein that blocks growth factor deprivation-induced apoptosis of lymphocytes in vitro. These results argue that the silencing of the T cell response to acute infection may not be a result simply of growth factor deprivation. The susceptibility of activated T cells to apoptotic death, which has previously been associated with virus-induced immune deficiency, may therefore also explain the en masse elimination of the expanded lymphocyte pool subsequent to an acute viral infection.

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 (3.9M), 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 79
79
icon of scanned page 80
80
icon of scanned page 81
81
icon of scanned page 82
82
icon of scanned page 83
83
icon of scanned page 84
84
icon of scanned page 85
85
icon of scanned page 86
86
icon of scanned page 87
87
icon of scanned page 88
88
icon of scanned page 89
89
icon of scanned page 90
90
icon of scanned page 91
91
 

Images in this article

Figure 1

Figure 1
on p.82

Figure 2

Figure 2
on p.83

Figure 4

Figure 4
on p.85

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.

  • Doherty PC, Zinkernagel RM. T-cell-mediated immunopathology in viral infections. Transplant Rev. 1974;19(0):89–120. [PubMed] [Google Scholar]
  • Buchmeier MJ, Welsh RM, Dutko FJ, Oldstone MB. The virology and immunobiology of lymphocytic choriomeningitis virus infection. Adv Immunol. 1980;30:275–331. [PubMed] [Google Scholar]
  • Doherty PC, Allan W, Eichelberger M, Carding SR. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annu Rev Immunol. 1992;10:123–151. [PubMed] [Google Scholar]
  • Lukacher AE, Braciale VL, Braciale TJ. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med. 1984 Sep 1;160(3):814–826. [PMC free article] [PubMed] [Google Scholar]
  • Ando K, Guidotti LG, Wirth S, Ishikawa T, Missale G, Moriyama T, Schreiber RD, Schlicht HJ, Huang SN, Chisari FV. Class I-restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. J Immunol. 1994 Apr 1;152(7):3245–3253. [PubMed] [Google Scholar]
  • Zinkernagel RM, Welsh RM. H-2 compatibility requirement for virus-specific T cell-mediated effector functions in vivo. I. Specificity of T cells conferring antiviral protection against lymphocytic choriomeningitis virus is associated with H-2K and H-2D. J Immunol. 1976 Nov;117(5 Pt 1):1495–1502. [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]
  • Razvi ES, Welsh RM, McFarland HI. 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]
  • Duke RC, Cohen JJ. 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]
  • 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]
  • Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. [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]
  • 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]
  • Razvi ES, Welsh RM. 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. [PMC free article] [PubMed] [Google Scholar]
  • Strasser A, Harris AW, Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. [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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed] [Google Scholar]
  • Miyawaki T, Uehara T, Nibu R, Tsuji T, Yachie A, Yonehara S, Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992 Dec 1;149(11):3753–3758. [PubMed] [Google Scholar]
  • Crispe IN. Fatal interactions: Fas-induced apoptosis of mature T cells. Immunity. 1994 Aug;1(5):347–349. [PubMed] [Google Scholar]
  • Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. [PubMed] [Google Scholar]
  • Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. [PubMed] [Google Scholar]
  • Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, 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. [PubMed] [Google Scholar]
  • Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. [PubMed] [Google Scholar]
  • Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. [PubMed] [Google Scholar]
  • Deng G, Podack ER. Suppression of apoptosis in a cytotoxic T-cell line by interleukin 2-mediated gene transcription and deregulated expression of the protooncogene bcl-2. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2189–2193. [PMC free article] [PubMed] [Google Scholar]
  • Moss DJ, Bishop CJ, Burrows SR, Ryan JM. T lymphocytes in infectious mononucleosis. I. T cell death in vitro. Clin Exp Immunol. 1985 Apr;60(1):61–69. [PMC free article] [PubMed] [Google Scholar]
  • Savill J, Fadok V, Henson P, Haslett C. Phagocyte recognition of cells undergoing apoptosis. Immunol Today. 1993 Mar;14(3):131–136. [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]
  • Alderson MR, Armitage RJ, Maraskovsky E, Tough TW, Roux E, Schooley K, Ramsdell F, Lynch DH. Fas transduces activation signals in normal human T lymphocytes. J Exp Med. 1993 Dec 1;178(6):2231–2235. [PMC free article] [PubMed] [Google Scholar]
  • Kobayashi S, Hirano T, Kakinuma M, Uede T. Transcriptional repression and differential splicing of Fas mRNA by early transposon (ETn) insertion in autoimmune lpr mice. Biochem Biophys Res Commun. 1993 Mar 15;191(2):617–624. [PubMed] [Google Scholar]
  • Singer GG, Abbas AK. 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. [PubMed] [Google Scholar]
Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology