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  • The EMBO Journal (2000) 19, 5418 - 5428
  • doi:10.1093/emboj/19.20.5418

MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly

Tim H. Holmström1,2,3, Ingo Schmitz4, Thomas S. Söderström1,3, Minna Poukkula1,5, Victoria L. Johnson6, Sek C. Chow6, Peter H. Krammer4 and John E. Eriksson1,5

  1. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, PO Box 123, FIN-20521 Turku, Finland
  2. Turku Graduate School of Biomedical Sciences, University of Turku and Åbo Akademi University, FIN-20520 Turku, Finland
  3. Department of Biology, Åbo Akademi University, FIN-20520 Turku, Finland
  4. Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  5. Department of Biology, University of Turku, FIN-20014 Turku, Finland
  6. Centre for Mechanism of Human Toxicity, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK

Correspondence to:

John E. Eriksson, E-mail: john.eriksson@utu.fi

Received 14 June 2000; Accepted 24 August 2000; Revised 21 August 2000

When T cells are activated, the expression of the CD95 ligand is elevated, with the purpose of inducing apoptosis in target cells and to later eliminate the activated T cells. We have shown previously that mitogen-activated protein kinase (MAPK or ERK) signaling suppresses CD95-mediated apoptosis in different cellular systems. In this study we examined whether MAPK signaling controls the persistence and CD95-mediated termination of an immune response in activated T cells. Our results show that activation of Jurkat T cells through the T cell receptor immediately suppresses CD95-mediated apoptosis, and that this suppression is mediated by MAPK activation. During the phase of elevated MAPK activity, the activation of caspase-8 and Bid is inhibited, whereas the assembly of a functional death-inducing signaling complex (DISC) is not affected. These results explain the resistance to CD95 responses observed during the early phase of T cell activation and suggest that MAPK-activation deflects DISC signaling from activating caspase-8 and Bid. The physiological relevance of the results was confirmed in activated primary peripheral T cells, in which inhibition of MAPK signaling markedly sensitized the cells to CD95-mediated apoptosis.

  • Keywords:

    • apoptosis,
    • death receptor,
    • MAP kinase,
    • T cell activation,
    • T cell receptor