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-Mediated Signals Enhance CD4+ T Cell Survival by Up-Regulating Bcl-xL1
Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612
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-xL to enhance T cell survival intrinsically. We show in this study that protein kinase C (PKC)-
is required for enhancing the survival of activated CD4+ T cells by up-regulating Bcl-xL. In response to TCR stimulation, CD4+ PKC-–/– T cells failed to up-regulate Bcl-xL, and underwent accelerated apoptosis via a caspase- and mitochondria-dependent pathway. Similar to PKC--deficient primary CD4+ T cells, small interfering RNA-mediated knockdown of PKC- in Jurkat cells also resulted in apoptosis upon TCR stimulation. Forced expression of Bcl-xL was sufficient to inhibit apoptosis observed in PKC- knockdown cells. Furthermore, ectopic expression of PKC- stimulated a reporter gene driven by a mouse Bcl-xL promoter. Whereas an inactive form of PKC- or knockdown of endogenous PKC- led to inhibition of Bcl-xL reporter. PKC--mediated activation of Bcl-xL reporter was inhibited by dominant-negative I
B kinase 
or dominant-negative AP-1. Thus, the PKC--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-xL levels through NF-B and AP-1 pathways.
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