Up-regulation of c-FLIP short by NFAT contributes to apoptosis resistance of short-term activated T cells.
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-FLIP(short), whereas expression of c-FLIP(long) was only marginally modulated. In contrast to the general view that c-FLIP transcription is controlled predominantly by nuclear factor-kappaB (NF-kappaB), induction of c-FLIP(short) 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.
Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany.
Nana
N
Ueffing
Marc
M
Schuster
Eric
E
Keil
Klaus
K
Schulze-Osthoff
Ingo
I
Schmitz
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms; D034622:RNA Interference; D013601:T-Lymphocytes / Q000166:cytology*; D013997:Time Factors; D015854:Up-Regulation
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D020033:Protein Isoforms