Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Aug 1, 1996; 184(2): 485–492.
PMCID: PMC2192715

Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL

Abstract

Experimental data suggest that negative selection of thymocytes can occur as a result of supraoptimal antigenic stimulation. It is unknown, however, whether such mechanisms are at work in mature CD8+ T lymphocytes. Here, we show that CD8+ effector cytotoxic T lymphocytes (CTL) are susceptible to proliferative inhibition by high dose peptide antigen, leading to apoptotic death mediated by TNF-alpha release. Such inhibition is not reflected in the cytolytic potential of the CTL, since concentrations of antigen that are inhibitory for proliferation promote efficient lysis of target cells. Thus, although CTL have committed to the apoptotic pathway, the kinetics of this process are such that CTL function can occur before death of the CTL. The concentration of antigen required for inhibition is a function of the CTL avidity, in that concentrations of antigen capable of completely inhibiting high avidity CTL maximally stimulate low avidity CTL. Importantly, the inhibition can be detected in both activated and resting CTL. Blocking studies demonstrate that the CD8 molecule contributes significantly to the inhibitory signal as the addition of anti-CD8 antibody restores the proliferative response. Thus, our data support the model that mature CD8+ CTL can accommodate an activation signal of restricted intensity, which, if surpassed, results in deletion of that cell.

Full Text

The Full Text of this article is available as a PDF (858K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. [PubMed]
  • von Boehmer H, Teh HS, Kisielow P. The thymus selects the useful, neglects the useless and destroys the harmful. Immunol Today. 1989 Feb;10(2):57–61. [PubMed]
  • Miller JF, Heath WR. Self-ignorance in the peripheral T-cell pool. Immunol Rev. 1993 Jun;133:131–150. [PubMed]
  • Jones LA, Chin LT, Longo DL, Kruisbeek AM. Peripheral clonal elimination of functional T cells. Science. 1990 Dec 21;250(4988):1726–1729. [PubMed]
  • Wieties K, Hammer RE, Jones-Youngblood S, Forman J. Peripheral tolerance in mice expressing a liver-specific class I molecule: inactivation/deletion of a T-cell subpopulation. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6604–6608. [PMC free article] [PubMed]
  • Zhang LI, Martin DR, Fung-Leung WP, Teh HS, Miller RG. Peripheral deletion of mature CD8+ antigen-specific T cells after in vivo exposure to male antigen. J Immunol. 1992 Jun 15;148(12):3740–3745. [PubMed]
  • Rocha B, von Boehmer H. Peripheral selection of the T cell repertoire. Science. 1991 Mar 8;251(4998):1225–1228. [PubMed]
  • McCormack JE, Callahan JE, Kappler J, Marrack PC. Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigen. J Immunol. 1993 May 1;150(9):3785–3792. [PubMed]
  • Aichele P, Brduscha-Riem K, Zinkernagel RM, Hengartner H, Pircher H. T cell priming versus T cell tolerance induced by synthetic peptides. J Exp Med. 1995 Jul 1;182(1):261–266. [PMC free article] [PubMed]
  • Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo VK, Weiner HL. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. 1995 Jul 13;376(6536):177–180. [PubMed]
  • Ferber I, Schönrich G, Schenkel J, Mellor AL, Hämmerling GJ, Arnold B. Levels of peripheral T cell tolerance induced by different doses of tolerogen. Science. 1994 Feb 4;263(5147):674–676. [PubMed]
  • Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. [PubMed]
  • Suzuki G, Kawase Y, Koyasu S, Yahara I, Kobayashi Y, Schwartz RH. Antigen-induced suppression of the proliferative response of T cell clones. J Immunol. 1988 Mar 1;140(5):1359–1365. [PubMed]
  • Critchfield JM, Racke MK, Zúiga-Pflücker JC, Cannella B, Raine CS, Goverman J, Lenardo MJ. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science. 1994 Feb 25;263(5150):1139–1143. [PubMed]
  • Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995 Sep 28;377(6547):348–351. [PubMed]
  • Alexander-Miller MA, Leggatt GR, Berzofsky JA. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4102–4107. [PMC free article] [PubMed]
  • Townsend AR, Rothbard J, Gotch FM, Bahadur G, Wraith D, McMichael AJ. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. [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]
  • Takahashi H, Cohen J, Hosmalin A, Cease KB, Houghten R, Cornette JL, DeLisi C, Moss B, Germain RN, Berzofsky JA. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. [PMC free article] [PubMed]
  • Shirai M, Pendleton CD, Berzofsky JA. Broad recognition of cytotoxic T cell epitopes from the HIV-1 envelope protein with multiple class I histocompatibility molecules. J Immunol. 1992 Mar 15;148(6):1657–1667. [PubMed]
  • Kozlowski S, Corr M, Takeshita T, Boyd LF, Pendleton CD, Germain RN, Berzofsky JA, Margulies DH. Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules. J Exp Med. 1992 Jun 1;175(6):1417–1422. [PMC free article] [PubMed]
  • Alexander MA, Damico CA, Wieties KM, Hansen TH, Connolly JM. Correlation between CD8 dependency and determinant density using peptide-induced, Ld-restricted cytotoxic T lymphocytes. J Exp Med. 1991 Apr 1;173(4):849–858. [PMC free article] [PubMed]
  • Sarin A, Adams DH, Henkart PA. Protease inhibitors selectively block T cell receptor-triggered programmed cell death in a murine T cell hybridoma and activated peripheral T cells. J Exp Med. 1993 Nov 1;178(5):1693–1700. [PMC free article] [PubMed]
  • Telford WG, King LE, Fraker PJ. Rapid quantitation of apoptosis in pure and heterogeneous cell populations using flow cytometry. J Immunol Methods. 1994 Jun 3;172(1):1–16. [PubMed]
  • Vitiello A, Heath WR, Sherman LA. Consequences of self-presentation of peptide antigen by cytolytic T lymphocytes. J Immunol. 1989 Sep 1;143(5):1512–1517. [PubMed]
  • Walden PR, Eisen HN. Cognate peptides induce self-destruction of CD8+ cytolytic T lymphocytes. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9015–9019. [PMC free article] [PubMed]
  • Dutz JP, Walden PR, Eisen HN. Effects of cognate peptides on cytolytic and proliferative activities of cloned cytotoxic T lymphocytes. Int Immunol. 1992 May;4(5):571–580. [PubMed]
  • Su MW, Walden PR, Golan DB, Eisen HN. Cognate peptide-induced destruction of CD8+ cytotoxic T lymphocytes is due to fratricide. J Immunol. 1993 Jul 15;151(2):658–667. [PubMed]
  • Takahashi H, Nakagawa Y, Leggatt GR, Ishida Y, Saito T, Yokomuro K, Berzofsky JA. Inactivation of human immunodeficiency virus (HIV)-1 envelope-specific CD8+ cytotoxic T lymphocytes by free antigenic peptide: a self-veto mechanism? J Exp Med. 1996 Mar 1;183(3):879–889. [PMC free article] [PubMed]
  • 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]
  • 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]
  • Russell JH, Manning DE, McCulley DE, Meleedy-Rey P. Antigen as a positive and negative regulator of proliferation in cytotoxic lymphocytes. A model for the differential regulation of proliferation and lytic activity. J Immunol. 1988 Mar 15;140(6):1796–1801. [PubMed]
  • 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]
  • 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]
  • Critchfield JM, Zúiga-Pflücker JC, Lenardo MJ. Parameters controlling the programmed death of mature mouse T lymphocytes in high-dose suppression. Cell Immunol. 1995 Jan;160(1):71–78. [PubMed]
  • Russell JH, Rush BJ, Abrams SI, Wang R. Sensitivity of T cells to anti-CD3-stimulated suicide is independent of functional phenotype. Eur J Immunol. 1992 Jun;22(6):1655–1658. [PubMed]
  • Ju ST, Panka DJ, Cui H, Ettinger R, el-Khatib M, Sherr DH, Stanger BZ, Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. [PubMed]
  • 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]
  • Speiser DE, Kyburz D, Stübi U, Hengartner H, Zinkernagel RM. Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection. J Immunol. 1992 Aug 1;149(3):972–980. [PubMed]
  • Pantaleo G, De Maria A, Koenig S, Butini L, Moss B, Baseler M, Lane HC, Fauci AS. CD8+ T lymphocytes of patients with AIDS maintain normal broad cytolytic function despite the loss of human immunodeficiency virus-specific cytotoxicity. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4818–4822. [PMC free article] [PubMed]

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

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...