Physiological roles of PKC alpha and theta in T lymphocytes

The human immune system controls and modulates major diseases that attract the highest healthcare costs in developed countries, e.g. (i) infectious disease and protective vaccination, (ii) inflammatory diseases e.g. arthritis, chronic obstructive pulmonary disease, asthma, (iii) cancer and autoimmune diseases, (iv) cardiovascular disorders e.g. arteriosclerosis, (v) body`s rejection of donated organs or bone marrow in transplantation, including future virus-based gene therapy approaches. Importantly, the delicate balance of attacking foreign pathogens and human chronic disease-associated immune dysfunctions (that cannot anymore be turned off) is regulated primarily by T lymphocytes. Thereby, lymphoid homeostasis is maintained by the dynamic regulation of lymphocyte activation, proliferation, programmed cell death, and tissue specific homing. The protein kinase C (PKC) family of serinehreonine protein kinase gene family has been extensively studied for over a decade and it is widely accepted in the scientific community that PKC function is crucial in T cell biology. Nevertheless, no detailed studies of the cellular functions attributed to critical PKC isotypes are available. Here, the physiological T cell functions of two most critical PKC family members are proposed to be investigated employing our ongoing mouse genetic (e.g. genetic elimination of T cell expressed PKC genes by homologous recombination) and complementary molecular T cell biology studies. Given the central role of T lymphocytes in immune responses, a more complete understanding of the complex (patho)physiological cellular functions of the PKC gene module may advance our fundamental understanding of cell-to-cell communication, as well as may lead to the discovery of unique aspects of T lymphocyte cell proliferation and differentiation. There are no doubts that the analysis of such higher levels of PKC gene function description uses, may implicate an enormous potential (in cooperation with pharmaceutical industry) for the discovery of innovative therapeutic drugs targeting the PKC module and its surrogate effectors with improved efficacy and selectivity.

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 the AGC family of protein serinehreonine kinases as key players mediating cell growth regulation. To achieve these aims we apply modern biochemical, molecular, cellular and mouse genetic approaches. The underlying long term goal of our work is not only to understand their PKC isotype selective functions in signal transduction pathways in lymphocytes but also 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. Our project work relates to the biochemical, molecular and functional analysis of signal transducing AGC-protein S/T kinases. Thereby we focused on the physiological and non-redundant functions of the PKC gene products in haematopoietic cells, particularly T cells. 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. Next to the established important role of PKC as regulator of T cell fate, several other PKC isotypes are also expressed in T cells at a high level. We here have determined the physiological and non-redundant functions of PKCß , e , d and and isotypes in T cells (with emphasis on our mouse genetic studies). Additionally cellular regulation and effector pathways as well as physiological functions of PKC have been discovered. While PKCß , e , d and appear to be dispensable during cellular activation of primary CD3 + T cells, PKCa and PKC take critical parts in signalling pathways that are necessary for full antigen receptor mediated T cell activation and T lymphocyte immunity.