The Critical Role of Protein Kinase C-θ in Fas/Fas Ligand-Mediated Apoptosis

Abstract

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-θ (PKC-θ), superantigen (staphylococcal enterotoxin B)-induced deletion of Vβ8+ CD4+ T cells was defective in PKC-θ−/− mice. In response to staphylococcal enterotoxin B challenge, up-regulation of FasL, but not Fas, was significantly reduced in PKC-θ−/− mice. PKC-θ is thus required for maximum up-regulation of FasL in vivo. We further show that stimulation of FasL expression depends on PKC-θ-mediated activation of NF-AT pathway. In addition, PKC-θ−/− T cells displayed resistance to Fas-mediated apoptosis as well as activation-induced cell death (AICD). In the absence of PKC-θ, 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-θ−/− T cells were restored in the presence of high concentration of IL-2, a critical factor required for potentiating T cells for AICD. PKC-θ is thus required for promoting FasL expression and for potentiating Fas-mediated apoptosis.