PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors

Protein kinase C-theta (PKC theta) is a key enzyme in T lymphocytes, where it plays an important role in signal transduction downstream of the activated T cell antigen receptor (TCR) and the CD28 costimulatory receptor. Interest in PKC theta as a potential drug target has increased following recent findings that PKC theta is essential for harmful inflammatory responses mediated by Th2 (allergies) and Th17 (autoimm unity) cells as well as for graft-versus-host disease (GvHD) and allograft rejection, but is dispensable for beneficial responses such as antiviral immunity and graft-versus-leukemia (GyL) response. TCR/CD28 engagement triggers the translocation of the cytosolic PKC theta to the plasma membrane (PM), where it localizes at the center of the immunological synapse (IS), which forms at the contact site between an antigen-specific T cell and antigen-presenting cells (APC). However, the molecular basis for this unique localization, and whether it is required for its proper function have remained unresolved issues until recently. Our recent study resolved these questions by demonstrating that the unique V3 (hinge) domain of PKC theta and, more specifically, a proline-rich motif within this domain, is essential and sufficient for its localization at the IS, where it is anchored to the cytoplasmic tail of CD28 via an indirect mechanism involving Lck protein tyrosine kinase (PTK) as an intermediate. Importantly, the association of PKC theta with CD28 is essential not only for IS localization, but also for PKC theta-mediated activation of downstream signaling pathways, including the transcription factors NE-kappa B and NE-AT which are essential for productive T cell activation. Hence, interference with formation of the PKC theta-Lck-CD28 complex provides a promising basis for the design of novel, clinically useful allosteric PKC theta inhibitors. An additional recent study demonstrated that TCR triggering activates the germinal center kinase (GSK)-like kinase (GLK) and induces its association with the SLP-76 adaptor at the IS, where GLK phosphorylates the activation loop of PKC theta, converting it into an active enzyme. This recent progress, coupled with the need to study the biology of PKC theta in human T cells, is likely to facilitate the development of PKC theta-based therapeutic modalities for T cell-mediated diseases.