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PKCq

PKC enzymes play critical roles in the differentiation and proliferation of many cell types, including T cells, and in the response to diverse stimuli. Little is known, however, about the substrate specificity and role of individual PKC isoforms in distinct activation and developmental events in T cells. In 1993, we cloned and identified a novel PKC isoform, PKCq. It is characterized by a unique tissue distribution, i.e., in skeletal muscle, lymphoid organs, and hematopoietic cell lines, in particular T cells. PKCq plays an important role in T cell activation: It selectively activates the transcription factors AP-1 and NF-kB, and integrates TCR and CD28 signals, which lead to activation of the CD28 response element (RE) in the interleukin-2 (IL-2) gene promoter. PKCq also localizes to the center of the T cell immunological synapse (IS) that forms at the contact area between antigen-specific T cells and antigen-presenting cells, and serves as a platform for the transduction of activation signals. Consistent with its important role in T cell activation, mature T cells from PKCq-deficient mice display severely reduced proliferation and IL-2 production, along with impaired activation of NF-kB, AP-1 and NFAT. However, the role of PKCq in T cells is selective since it is required for allergic response mediated by T helper 2 (Th2) cells and autoimmune diseases mediated by Th17 cells, but is largely dispensable for anti-viral immunity. As a result of this selectivity, as well as its relatively specific T cell expression, PKCq has become an attractive drug target.

Other studies on PKCq have recently resolved some enigmas that have dominated the field for a long time, namely, what is the molecular basis for the selective recruitment of this enzyme to the center of the T cell IS, and is this localization essential for the ability of PKCq to activate T cells. Indeed, we found that PKCq‘s unique localization results from its physical association with CD28, a major T cell costimulatory receptor and, furthermore, that a PKCq mutant that does not associate with CD28 fails to activate T cells. These findings form a rational basis for the design of molecular entities that will block the PKCq-CD28 interaction and, therefore, will potentially have the desired effect of inhibiting allergic responses and autoimmune diseases.

We current continue these studies with particular emphasis on the role of PKCq in regulatory T (Treg) cells and in human T cells.