Analysis of PKCalpha-mediated regulation of TGFbeta receptor signaling in T cells

The immune system ensures protection from infectious diseases and also performs surveillance of tumor cells. For more then a decade, the major research topic of the group of Gottfried Baier relates to the biochemical, molecular and functional analysis of signal transducing S/T protein kinase family Protein Kinase C (PKC) within the haematopoietic system. Recently, the Transforming Growth Factor (TGF)beta receptor (TGFbetaR) signaling has been established to exert an essential and T cell intrinsic role in controlling immune responses and is intensely discussed as an emerging key mediator having causal implications in various immunological diseases. Based on our very recent experimental work, PKCalpha-deficient TH17 cells fail to mount appropriate IL-17A responses in vitro and fail to induce TH17-dependent experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Mechanistically, our data suggest that PKCalpha may set the threshold for TGFbetaR signaling of CD4+ T cell effector functions via a novel PKCalpha/TGFbetaR/SMAD2/3 candidate signaling axis. Furthermore, in nave CD4+ T cells, we observe a physical interaction and close proximity between PKCalpha with TGFbetaRI, employing co-immunoprecipitation and subcellular co-localization analysis. Thus and as the rational basis of this grant proposal, we have discovered a PKCalpha isotype-selective function in the regulation of TGFbetaR-induced IL-17A activation responses of CD4+ TH17 cells. Because the mode of action of PKCalpha as T cell intrinsic intermediate in this pathway remains unresolved, we propose to now further validate our findings as well as dissect the upstream and downstream signaling mechanisms of this PKCalphamediated candidate pathway in TH17 cell biology. To achieve these aims we apply modern biochemical, molecular, cellular and mouse genetic approaches. The underlying goal of the work is to better understand key 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.

The immune system ensures protection from infectious diseases and also performs surveillance of tumor cells. For more than a decade, the major research topic of the group of Gottfried Baier relates to the biochemical, molecular and functional analysis of signal transducing S/T protein kinase family Protein Kinase C (PKC) within the haematopoietic system. The Transforming Growth Factor (TGF)beta receptor (TGFbetaR) signalling has been established to exert an essential and T cell intrinsic role in controlling immune responses and is intensely discussed as an emerging key mediator having causal implications in various immunological diseases. Based on our experimental work, PKCalpha-deficient TH17 cells fail to mount appropriate IL-17A responses in vitro and fail to induce TH17-dependent experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Mechanistically, our data validate PKCalpha as threshold regulator for TGFbetaR signalling of CD4+ T cell effector functions via a novel PKCalpha/TGFbetaR/SMAD2/3 signalling axis. Furthermore, in nave CD4+ T cells, we observe a physical interaction and close proximity between PKCalpha with TGFbetaRI, employing co-immunoprecipitation and subcellular co-localization analysis. Thus and as the rational basis of our work, we have discovered a PKCalpha isotype-selective function in the regulation of TGFbetaR-induced IL-17A activation responses of CD4+ TH17 cells. Because the mode of action of PKCalpha and its family members PKCbeta and PKCtheta as T cell intrinsic intermediate have been unresolved, we dissected their signalling mechanisms and downstream effector pathway in T cell biology employing both modern biochemical, molecular, cellular and mouse genetic approaches as well as immune disease mouse models ranging form multiple sclerosis, colitis to cancer. The long-term goal of our work is to better understand these key PKC mediated signal transduction pathways in T lymphocytes and to use this information to develop strategies to manipulate the immune response, either for immunosuppression in autoimmune diseases or for augmentation in cancer.