Search tips
Search criteria 


Logo of jexpmedHomeEditorsContactInstructions for Authors
J Exp Med. 1996 October 1; 184(4): 1543–1547.
PMCID: PMC2192809

Perforin and Fas killing by CD8+ T cells limits their cytokine synthesis and proliferation


During an immune response, effector CD8+ T cells can kill infected cells by the perforin-dependent pathway. In comparison to CD4+ T cells, which are major sources of cytokines, normal CD8+ T cells produced less interleukin 2 and interferon gamma, and proliferated less vigorously after antigenic stimulation. Killing of target cells was a major cause of these reduced responses, since perforin-deficient CD8+ T cells showed substantially increased cytokine synthesis and proliferation. Cytotoxicity by the alternate Fas pathway also resulted in self- limitation of CD8+ T cell cytokine synthesis. This relationship between cytotoxicity and cytokine synthesis may regulate CD8+ T function in different phases of an immune response.

Full Text

The Full Text of this article is available as a PDF (484K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allison JP. CD28-B7 interactions in T-cell activation. Curr Opin Immunol. 1994 Jun;6(3):414–419. [PubMed]
  • Stout RD, Bottomly K. Antigen-specific activation of effector macrophages by IFN-gamma producing (TH1) T cell clones. Failure of IL-4-producing (TH2) T cell clones to activate effector function in macrophages. J Immunol. 1989 Feb 1;142(3):760–765. [PubMed]
  • Vitetta ES, Fernandez-Botran R, Myers CD, Sanders VM. Cellular interactions in the humoral immune response. Adv Immunol. 1989;45:1–105. [PubMed]
  • Swoboda R, Bommhardt U, Schimpl A. Regulation of lymphokine expression in T cell activation. I. Rapid loss of interleukin-specific RNA after removal of the stimulating signal. Eur J Immunol. 1991 Jul;21(7):1691–1695. [PubMed]
  • Wagner H, Röllinghoff M. T-T-cell interactions during the vitro cytotoxic allograft responses. I. Soluble products from activated Lyl+ T cells trigger autonomously antigen-primed Ly23+ T cells to cell proliferation and cytolytic activity. J Exp Med. 1978 Dec 1;148(6):1523–1538. [PMC free article] [PubMed]
  • Nabholz M, Engers HD, Collavo D, North M. Cloned T-cell lines with specific cytolytic activity. Curr Top Microbiol Immunol. 1978;81:176–187. [PubMed]
  • Glasebrook AL, Fitch FW. T-cell lines which cooperate in generation of specific cytolytic activity. Nature. 1979 Mar 8;278(5700):171–173. [PubMed]
  • von Boehmer H, Hengartner H, Nabholz M, Lernhardt W, Schreier MH, Haas W. Fine specificity of a continuously growing killer cell clone specific for H-Y antigen. Eur J Immunol. 1979 Aug;9(8):592–597. [PubMed]
  • Gillis S, Smith KA. Long term culture of tumour-specific cytotoxic T cells. Nature. 1977 Jul 14;268(5616):154–156. [PubMed]
  • Widmer MB, Bach FH. Antigen-driven helper cell-independent cloned cytolytic T lymphocytes. Nature. 1981 Dec 24;294(5843):750–752. [PubMed]
  • Von Boehmer H, Turton K. Autonomously proliferating K/D-restricted cytolytic T cell clones. Eur J Immunol. 1983 Feb;13(2):176–179. [PubMed]
  • Wee SL, Chen LK, Strassmann G, Bach FH. Helper cell-independent cytotoxic clones in man. J Exp Med. 1982 Dec 1;156(6):1854–1859. [PMC free article] [PubMed]
  • Croft M, Carter L, Swain SL, Dutton RW. Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med. 1994 Nov 1;180(5):1715–1728. [PMC free article] [PubMed]
  • Fong TA, Mosmann TR. Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines. J Immunol. 1990 Mar 1;144(5):1744–1752. [PubMed]
  • Sad S, Marcotte R, Mosmann TR. Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity. 1995 Mar;2(3):271–279. [PubMed]
  • Zinkernagel RM. Immunology taught by viruses. Science. 1996 Jan 12;271(5246):173–178. [PubMed]
  • Glimcher LH, Sharrow SO, Paul WE. Serologic and functional characterization of a panel of antigen-presenting cell lines expressing mutant I-A class II molecules. J Exp Med. 1983 Nov 1;158(5):1573–1588. [PMC free article] [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]
  • Sad S, Mosmann TR. Interleukin (IL) 4, in the absence of antigen stimulation, induces an anergy-like state in differentiated CD8+ TC1 cells: loss of IL-2 synthesis and autonomous proliferation but retention of cytotoxicity and synthesis of other cytokines. J Exp Med. 1995 Nov 1;182(5):1505–1515. [PMC free article] [PubMed]
  • Mosmann TR, Fong TA. Specific assays for cytokine production by T cells. J Immunol Methods. 1989 Jan 17;116(2):151–158. [PubMed]
  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed]
  • Kägi D, Ledermann B, Bürki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. [PubMed]
  • Walsh CM, Matloubian M, Liu CC, Ueda R, Kurahara CG, Christensen JL, Huang MT, Young JD, Ahmed R, Clark WR. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10854–10858. [PubMed]
  • Kojima H, Shinohara N, Hanaoka S, Someya-Shirota Y, Takagaki Y, Ohno H, Saito T, Katayama T, Yagita H, Okumura K, et al. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity. 1994 Aug;1(5):357–364. [PubMed]
  • Lowin B, Hahne M, Mattmann C, Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature. 1994 Aug 25;370(6491):650–652. [PubMed]
  • Kägi D, Vignaux F, Ledermann B, Bürki K, Depraetere V, Nagata S, Hengartner H, Golstein P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994 Jul 22;265(5171):528–530. [PubMed]
  • Rothstein TL, Wang JK, Panka DJ, Foote LC, Wang Z, Stanger B, Cui H, Ju ST, Marshak-Rothstein A. Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells. Nature. 1995 Mar 9;374(6518):163–165. [PubMed]
  • Valitutti S, Müller S, Dessing M, Lanzavecchia A. Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med. 1996 Apr 1;183(4):1917–1921. [PMC free article] [PubMed]
  • Kägi D, Seiler P, Pavlovic J, Ledermann B, Bürki K, Zinkernagel RM, 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. [PubMed]
  • Harty JT, Schreiber RD, Bevan MJ. CD8 T cells can protect against an intracellular bacterium in an interferon gamma-independent fashion. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11612–11616. [PubMed]
  • Kirberg J, Bruno L, von Boehmer H. CD4+8- help prevents rapid deletion of CD8+ cells after a transient response to antigen. Eur J Immunol. 1993 Aug;23(8):1963–1967. [PubMed]
  • Rees MA, Rosenberg AS, Munitz TI, Singer A. In vivo induction of antigen-specific transplantation tolerance to Qa1a by exposure to alloantigen in the absence of T-cell help. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2765–2769. [PubMed]
  • Matloubian M, Concepcion RJ, Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol. 1994 Dec;68(12):8056–8063. [PMC free article] [PubMed]
  • Williamson JS, Stohlman SA. Effective clearance of mouse hepatitis virus from the central nervous system requires both CD4+ and CD8+ T cells. J Virol. 1990 Sep;64(9):4589–4592. [PMC free article] [PubMed]

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