Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1995 Jan 1; 181(1): 71–77.
PMCID: PMC2191813

Fas ligand mediates activation-induced cell death in human T lymphocytes


A significant proportion of previously activated human T cells undergo apoptosis when triggered through the CD3/T cell receptor complex, a process termed activation-induced cell death (AICD). Ligation of Fas on activated T cells by either Fas antibodies or recombinant human Fas- ligand (Fas-L) also results in cytolysis. We demonstrate that these two pathways of apoptosis are causally related. Stimulation of previously activated T cells resulted in the expression of Fas-L mRNA and lysis of Fas-positive target cells. Fas-L antagonists inhibited AICD of T cell clones and staphylococcus enterotoxin B (SEB)-specific T cell lines. The data indicate AICD in previously stimulated T cells is mediated by Fas/Fas-L interactions.

Full Text

The Full Text of this article is available as a PDF (2.8M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • 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]
  • 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]
  • 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]
  • Wesselborg S, Janssen O, Kabelitz D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol. 1993 May 15;150(10):4338–4345. [PubMed]
  • Rahelu M, Williams GT, Kumararatne DS, Eaton GC, Gaston JS. Human CD4+ cytolytic T cells kill antigen-pulsed target T cells by induction of apoptosis. J Immunol. 1993 Jun 1;150(11):4856–4866. [PubMed]
  • Radvanyi LG, Mills GB, Miller RG. Religation of the T cell receptor after primary activation of mature T cells inhibits proliferation and induces apoptotic cell death. J Immunol. 1993 Jun 15;150(12):5704–5715. [PubMed]
  • D'Adamio L, Awad KM, Reinherz EL. Thymic and peripheral apoptosis of antigen-specific T cells might cooperate in establishing self tolerance. Eur J Immunol. 1993 Mar;23(3):747–753. [PubMed]
  • Kabelitz D, Pohl T, Pechhold K. Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol Today. 1993 Jul;14(7):338–339. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Trauth BC, Klas C, Peters AM, Matzku S, Möller P, Falk W, Debatin KM, Krammer PH. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989 Jul 21;245(4915):301–305. [PubMed]
  • Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. [PubMed]
  • Owen-Schaub LB, Yonehara S, Crump WL, 3rd, Grimm EA. DNA fragmentation and cell death is selectively triggered in activated human lymphocytes by Fas antigen engagement. Cell Immunol. 1992 Mar;140(1):197–205. [PubMed]
  • Mapara MY, Bargou R, Zugck C, Döhner H, Ustaoglu F, Jonker RR, Krammer PH, Dörken B. APO-1 mediated apoptosis or proliferation in human chronic B lymphocytic leukemia: correlation with bcl-2 oncogene expression. Eur J Immunol. 1993 Mar;23(3):702–708. [PubMed]
  • 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]
  • Ramsdell F, Seaman MS, Miller RE, Tough TW, Alderson MR, Lynch DH. gld/gld mice are unable to express a functional ligand for Fas. Eur J Immunol. 1994 Apr;24(4):928–933. [PubMed]
  • Lynch DH, Watson ML, Alderson MR, Baum PR, Miller RE, Tough T, Gibson M, Davis-Smith T, Smith CA, Hunter K, et al. The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity. 1994 May;1(2):131–136. [PubMed]
  • Idzerda RL, March CJ, Mosley B, Lyman SD, Vanden Bos T, Gimpel SD, Din WS, Grabstein KH, Widmer MB, Park LS, et al. Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J Exp Med. 1990 Mar 1;171(3):861–873. [PMC free article] [PubMed]
  • Smith CA, Gruss HJ, Davis T, Anderson D, Farrah T, Baker E, Sutherland GR, Brannan CI, Copeland NG, Jenkins NA, et al. CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell. 1993 Jul 2;73(7):1349–1360. [PubMed]
  • Dive C, Gregory CD, Phipps DJ, Evans DL, Milner AE, Wyllie AH. Analysis and discrimination of necrosis and apoptosis (programmed cell death) by multiparameter flow cytometry. Biochim Biophys Acta. 1992 Feb 3;1133(3):275–285. [PubMed]
  • Goodwin RG, Alderson MR, Smith CA, Armitage RJ, VandenBos T, Jerzy R, Tough TW, Schoenborn MA, Davis-Smith T, Hennen K, et al. Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor. Cell. 1993 May 7;73(3):447–456. [PubMed]
  • Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992 Nov;11(11):3887–3895. [PMC free article] [PubMed]
  • Carlsson R, Fischer H, Sjögren HO. Binding of staphylococcal enterotoxin A to accessory cells is a requirement for its ability to activate human T cells. J Immunol. 1988 Apr 15;140(8):2484–2488. [PubMed]
  • Fleischer B, Schrezenmeier H. T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells. J Exp Med. 1988 May 1;167(5):1697–1707. [PMC free article] [PubMed]
  • Kawabe Y, Ochi A. Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med. 1990 Oct 1;172(4):1065–1070. [PMC free article] [PubMed]
  • Rellahan BL, Jones LA, Kruisbeek AM, Fry AM, Matis LA. In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B. J Exp Med. 1990 Oct 1;172(4):1091–1100. [PMC free article] [PubMed]
  • 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]
  • MacDonald HR, Baschieri S, Lees RK. 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. [PubMed]
  • Kabelitz D, Wesselborg S. Life and death of a superantigen-reactive human CD4+ T cell clone: staphylococcal enterotoxins induce death by apoptosis but simultaneously trigger a proliferative response in the presence of HLA-DR+ antigen-presenting cells. Int Immunol. 1992 Dec;4(12):1381–1388. [PubMed]
  • Wesselborg S, Kabelitz D. Activation-driven death of human T cell clones: time course kinetics of the induction of cell shrinkage, DNA fragmentation, and cell death. Cell Immunol. 1993 Apr 15;148(1):234–241. [PubMed]
  • 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]
  • Adachi M, Watanabe-Fukunaga R, Nagata S. Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1756–1760. [PMC free article] [PubMed]
  • Singer PA, Balderas RS, McEvilly RJ, Bobardt M, Theofilopoulos AN. 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. [PMC free article] [PubMed]
  • Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. [PubMed]
  • Damle NK, Leytze G, Klussman K, Ledbetter JA. Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18-dependent mechanism. Eur J Immunol. 1993 Jul;23(7):1513–1522. [PubMed]
  • Russell JH, 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. [PMC free article] [PubMed]
  • Bossu P, Singer GG, Andres P, Ettinger R, Marshak-Rothstein A, Abbas AK. Mature CD4+ T lymphocytes from MRL/lpr mice are resistant to receptor-mediated tolerance and apoptosis. J Immunol. 1993 Dec 15;151(12):7233–7239. [PubMed]
  • Russell JH, 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. [PubMed]
  • 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]
  • Stalder T, Hahn S, Erb P. Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol. 1994 Feb 1;152(3):1127–1133. [PubMed]
  • Rouvier E, Luciani MF, Golstein P. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med. 1993 Jan 1;177(1):195–200. [PMC free article] [PubMed]
  • 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]
  • 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]
  • 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. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    NCBI Bookshelf books that cite the current articles.
  • Compound
    PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
  • Gene
    Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence and PMC links.
  • GEO Profiles
    GEO Profiles
    Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
  • HomoloGene
    HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
  • MedGen
    Related information in MedGen
  • Nucleotide
    Primary database (GenBank) nucleotide records reported in the current articles as well as Reference Sequences (RefSeqs) that include the articles as references.
  • Protein
    Protein translation features of primary database (GenBank) nucleotide records reported in the current articles as well as Reference Sequences (RefSeqs) that include the articles as references.
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...