Protein kinase C-θ-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL

Productive engagement of TCR results in delivering signals required for T cell proliferation as well as T cell survival. Blocking TCR-mediated survival signals, T cells undergo apoptosis instead of proliferation upon TCR stimulation. During the activation process, T cells produce IL-2, which acts as an extrinsic survival factor. In addition, TCR stimulation results in up-regulation of Bcl-x(L) to enhance T cell survival intrinsically. We show in this study that protein kinase C (PKC)-theta is required for enhancing the survival of activated CD4(+) T cells by up-regulating Bcl-x(L). In response to TCR stimulation, CD4(+) PKC-theta(-/-) T cells failed to up-regulate Bcl-x(L), and underwent accelerated apoptosis via a caspase- and mitochondria-dependent pathway. Similar to PKC-theta-deficient primary CD4(+) T cells, small interfering RNA-mediated knockdown of PKG-theta in Jurkat cells also resulted in apoptosis upon TCR stimulation. Forced expression of Bcl-x(L) was sufficient to inhibit apoptosis observed in PKC-theta knockdown cells. Furthermore, ectopic expression of PKG-theta stimulated a reporter gene driven by a mouse Bcl-x(L) promoter. Whereas an inactive form of PKG-theta or knockdown of endogenous PKG-theta led to inhibition of Bcl-x(L) reporter. PKC-theta-mediated activation of Bcl-x(L) reporter was inhibited by dominant-negative I kappa B kinase beta or dominant-negative AP-1. Thus, the PKC-theta-mediated signals may function not only in the initial activation of naive CD4(+) T cells, but also in their survival during T cell activation by regulating Bcl-x(L) levels through NF-kappa B and AP-1 pathways.