|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
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.
Submitted February 21, 2008
Institute of Molecular Medicine, University of Dusseldorf, Dusseldorf, Germany * Corresponding author; email: ingo-schmitz{at}uni-duesseldorf.de.
Upon encounter with pathogens, T cells activate a number of defense mechanisms, one of which is the upregulation of CD95 ligand (CD95L/FasL) that 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 anti-apoptotic molecules. We show here that, in contrast to naive or long-term activated T cells, short-term activated T cells strongly upregulate the caspase-8 inhibitor 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 predominantly controlled by nuclear factor of kappa B (NF-
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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 towards CD95L- as well as activation-induced apoptosis. Thus, the resistance of recently activated T cells crucially depends 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.
