Molecular Mechanisms and Functions of Protein Kinase Calpha (PKCalpha) in CD3+ T lymphocytes

To understand the physiology and pathophysiology of T cells, the most important effector cells of the immune system, it is necessary to elucidate the biochemical processes which are responsible for activation of these cells. Protein kinase Calpha (PKCa) is a key enyme in these signaling pathways leading to proliferation, cytokine secretion, cytoskeletal remodelling, and controlled cell death (apoptosis). PKCa is a member of the conventional PKCs (cPKCs) which require calcium and dicylglycerol for activation. It is highly expressed in lymphocytes of the T cell linage and translocates to the plasma membrane following T cell activation. To analyze the pathways PKCa is involved in, we started a cooperation with Michael Leitges, Hannover, who established a mouse model where the gene for PKCa is knocked out (knock-out mouse). Our recent analysis showed that these mice demonstrated a profound immune defect. During this project I want to find out how the molecular mechanisms of PKCa are and how they lead to the immune deficiency. These insights could contribute to a better knowledge of how the immune system works and in the end to establish strategies to modulate the immune system during e.g. autoimmune diseases.

The research group led by Dr. Christa Pfeifhofer-Obermair at the Section of Cell Genetics (Department of Medical Genetics, Molecular and Clinical Pharmacology), headed by Univ.- Prof. Gottfried Baier, concentrates on the molecular basis of the immune system especially on the Protein Kinase C Family which is essential for signalling in T-lymphocytes. After recognizing an antigen T-lymphocytes differentiate depending on the surrounding cytokine milieu into highly specialized effector T cells which are called iTreg, Th1, Th2, Th9, and Th17 effector T cells. Th17 effector T cells are characterized by the pro-inflammatory cytokine IL-17, which plays an important role in adaptive immunity against bacteria, fungi, and parasites, but also in the development of autoimmunity. The cytokine TGF is essential for Th17 cell differentiation. The TGF receptor is strongly regulated by phosphorylation, an important mechanism in the regulation of protein activities and signaling processes. TGF signalling is activated by binding of TGF to a receptor called TGFType-II-receptor (TGFRII). This leads to the recruitment of the TGFType-I-receptor (TGFRI), the phosphorylation of TGFRI by TGFRII and the phosphorylation of transcription factors SMAD2 and SMAD3 which activate the transcription of important target genes e.g. IL-17. The research group of Dr. Pfeifhofer-Obermair could identify the protein kinase C alpha (PKC?) as an important priming kinase leading to fast and successful activation of TGFRI. Inhibition of PKC? by gene knockout or by using pharmacological inhibitors of PKC? blocks the TGFR/SMAD signalling pathway in Th17 cells leading to a resistance to induction of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Recently studies of other research group could identify a correlation between genetical variants of PKC? and multiple sclerosis, independently confirming the important role of PKC? in the development of this disease. This first described direct and functionally crucial PKC?-TGFRI kinase cooperation extends the paradigm of TGF?RI regulation in Th17 cell biology.