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Blood, 1 August 2008, Vol. 112, No. 3, pp. 690-698. Prepublished online as a Blood First Edition Paper on May 28, 2008; DOI 10.1182/blood-2008-02-141382. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-02-141382v1 112/3/690    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Ueffing, N. Articles by Schmitz, I. PubMed PubMed Citation Articles by Ueffing, N. Articles by Schmitz, I. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Up-regulation of c-FLIPshort by NFAT contributes to apoptosis resistance of short-term activated T cells Nana Ueffing1, Marc Schuster1, Eric Keil1, Klaus Schulze-Osthoff1, and Ingo Schmitz1 1 Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany Upon encounter with pathogens, T cells activate several defense mechanisms, one of which is the up-regulation of CD95 ligand (CD95L/FasL) which induces apoptosis in sensitive target cells. Despite expression of the CD95 receptor, however, recently activated T cells are resistant to CD95L, presumably due to an increased expression of antiapoptotic molecules. We show here that, in contrast to naive or long-term activated T cells, short-term activated T cells strongly up-regulate the caspase-8 inhibitor, cellular FLICE-inhibitory protein (c-FLIP). Intriguingly, upon activation, T cells highly induced the short splice variant c-FLIPshort, whereas expression of c-FLIPlong was only marginally modulated. In contrast to the general view that c-FLIP transcription is controlled predominantly by nuclear factor-B (NF-B), induction of c-FLIPshort in T cells was primarily mediated by the calcineurin-nuclear factor of activated T cells (NFAT) pathway. Importantly, blockage of NFAT-mediated c-FLIP expression by RNA interference or inhibition of calcineurin rendered T cells sensitive toward CD95L, as well as activation-induced apoptosis. Thus, the resistance of recently activated T cells depends crucially on induction of c-FLIP expression by the calcineurin/NFAT pathway. Our findings imply that preventing autocrine CD95L signaling by c-FLIP facilitates T-cell effector function and an efficient immune response. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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