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The protein kinase C-theta (PKCθ) isoform is a member of the calcium-independent novel PKC subfamily of serine/threonine kinases. It is an essential regulatory enzyme in mature T lymphocytes, where it plays a key role in coupling the activated TCR and the CD28 costimulatory receptor to their downstream signaling pathways. TCR/ CD28 engagement induces the translocation of PKCθ to the center of the immunological synapse where it undergoes posttranslational modifications and becomes fully active. The activated PKCθ then initiates signaling pathways leading to the activation of transcription factors, including NF-κB, AP-1 and NF-AT that are essential for the survival, activation and differentiation of T cells. While PKCθ ablation was found to impair a wide range of in vitro responses of T cells, in vivo studies in Prkcq-/- mice revealed that distinct T cell subpopulations differ in their requirements for PKCθ and that PKCθ has a selective role in different immune responses. Thus, PKCθ participates in cellular mechanisms leading to excessive inflammatory responses, autoimmunity, and graft vs host (GvH) disease, but is dispensable for beneficial immune responses against viruses and during graft vs leukemia responses. These studies suggest that PKCθ may serve as a potential drug target for catalytic and allosteric inhibitors in selected T cell-mediated diseases, and that fine-tuning of PKCθ-dependent functions may help prevent autoimmunity and GvH, without impairing the ability of T cells to eradicate viral-infected and transformed cells.