The critical role of protein kinase C-theta in Fas/Fas ligand-mediated apoptosis.
A functional immune system not only requires rapid expansion of antigenic specific T cells, but also requires efficient deletion of clonally expanded T cells to avoid accumulation of T cells. Fas/Fas ligand (FasL)-mediated apoptosis plays a critical role in the deletion of activated peripheral T cells, which is clearly demonstrated by superantigen-induced expansion and subsequent deletion of T cells. In this study, we show that in the absence of protein kinase C-theta (PKC-theta), superantigen (staphylococcal enterotoxin B)-induced deletion of Vbeta8(+) CD4(+) T cells was defective in PKC-theta(-/-) mice. In response to staphylococcal enterotoxin B challenge, up-regulation of FasL, but not Fas, was significantly reduced in PKC-theta(-/-) mice. PKC-theta is thus required for maximum up-regulation of FasL in vivo. We further show that stimulation of FasL expression depends on PKC-theta-mediated activation of NF-AT pathway. In addition, PKC-theta(-/-) T cells displayed resistance to Fas-mediated apoptosis as well as activation-induced cell death (AICD). In the absence of PKC-theta, Fas-induced activation of apoptotic molecules such as caspase-8, caspase-3, and Bid was not efficient. However, AICD as well as Fas-mediated apoptosis of PKC-theta(-/-) T cells were restored in the presence of high concentration of IL-2, a critical factor required for potentiating T cells for AICD. PKC-theta is thus required for promoting FasL expression and for potentiating Fas-mediated apoptosis.
Manicassamy
Santhakumar
S
Department of Microbiology and Immunology, School of Medicine, University of Illinois, Chicago, IL 60612, USA.
Sun
Zuoming
Z
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D004768:Enterotoxins / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D004768:Enterotoxins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C031818:enterotoxin B, staphylococcal; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D053148:Caspase 3; D053181:Caspase 8