Mechanistic role of PKCtheta autophosphorylation at Thr219

The main function of mature T cells is to recognize and respond to foreign antigens by a complex activation process involving differentiation of the resting cell to a proliferating lymphoblast actively secreting immunoregulatory lymphokines or displaying targeted cytotoxicity, ultimately leading to recruitment of other cell types and initiation of an effective immune response. In order to understand the physiology and pathophysiology of T lymphocytes, it is necessary to decode the biochemical processes that integrate signals from antigen, cytokine and death receptors. The principal upon which our work is based is to explore the molecular role of the distinct member of the AGC family of protein serinehreonine kinases, PKCtheta. As our underlying working hypothesis, its intrinsic structural determinant, Thr-219 autophosphorylation, may serve as the key switch that mediates T cell activation and T lymphocyte immunity. The goal of our work is to understand the PKCtheta isotype-selective function in signal transduction pathways in lymphocytes. To achieve this ambitious aim we apply modern biochemical, molecular, cellular and mouse genetic approaches. We thereby plan to analyze the functional consequences of Thr-219 autophosphorylation during recruitment, activation and cellular function of PKCtheta in CD3 + T cells ex vivo as well as in immune responses in vivo. Secondly, we aim to biochemically identify signal-transducing molecules that assemble (via protein:protein interactions) into a potential PKCtheta multi-protein complex as key effectors during T cell activation linked to antigen receptor signaling and/or apoptosis resistance. We strongly believe that a greater mechanistic understanding of how signals are transmitted from the PKCtheta isotype, eliciting T cellular effector responses, will aid to develop strategies to manipulate the immune response, either for immunosuppression in autoimmune diseases, graft rejection as well as the inflammatory response or for augmentation in cancer.

The main function of mature T cells is to recognize and respond to foreign antigens by a complex activation process involving differentiation of the resting cell to a proliferating lymphoblast actively secreting immunoregulatory lymphokines or displaying targeted cytotoxicity, ultimately leading to recruitment of other cell types and initiation of an effective immune response. In order to understand the physiology and pathophysiology of T lymphocytes, it is necessary to decode the biochemical processes that integrate signals from antigen, cytokine, integrin and death receptors. The principal upon which our work is based is to explore and identify gene products of distinct members of protein serinehreonine kinases as key players mediating cell growth regulation. The underlying goal of the work is to understand their selective functions in signal transduction pathways in lymphocytes and to use this information to develop strategies to manipulate the immune response, either for immunosuppression in autoimmune diseases, graft rejection as well as the inflammatory response or for augmentation in cancer. To achieve these aims we apply modern biochemical, molecular, cellular and mouse genetic approaches. The major research topic of the group of G. Baier relates to the biochemical, molecular and functional analysis of signal transducing S/T protein kinase family PKC within the haematopoietic system. Our project work relates to the biochemical, molecular and functional analysis of signal transducing AGC-protein kinases. In spite of the large amount of information on PKC functions in various cell types and tissues, the characterization of the isotype selective functions of the entire PKC family in lymphoid cell lineages is far from complete. Thereby we focused on the physiological and non-redundant functions of the PKC gene products in T cells. We here have determined the physiological and non-redundant functions of PKCtheta, alpha and beta isotypes in T cells with emphasis on our mouse genetic studies. Additionally cellular regulation and effector pathways as well as physiological functions of these PKC isotypes have been discovered necessary for full antigen receptor mediated T cell activation and T lymphocyte immunity.