PKCtheta/Coronin 1A axis in CD4+ T cell subpopulations

T cell activation, differentiation as well as survival critically depend on molecular networks that translate external stimuli into cellular responses and thereby shape the outcome of immune reactions. However, T cell activation needs to be tightly regulated, since inappropriate T cell responses can lead to disease states such as the development of autoimmunity. The group of Professor Gottfried Baier at the Medical University of Innsbruck has shown over the last decade that members of the protein kinase family are crucially involved in T cell signaling pathways and play decisive roles in the nature of effector responses. Recently, the Baier laboratory has discovered Coronin 1A (Coro1A) as a novel interaction partner of PKCtheta in CD4 + T cells, acting as a positive regulator of the NF-kappaB pathway. In line with those observations, Dr. Kerstin Siegmund has identified Coro1A as a crucial modulator of autoimmune responses in a murine model of multiple sclerosis during her recent research at the University of Basel. Nonetheless, the physiological role and the precise molecular mechanisms of a potential PKCtheta/Coro1A axis with regard to T cell activation remain unknown. Therefore, we propose to analyze in detail the role of Coro1A in PKCtheta-mediated signal transduction in CD4 + T cell subsets in vitro, ex vivo and in vivo. Our working hypothesis is that PKCtheta in concert with Coro1A, as well as newly identified interaction partners, contributes to the signaling network controlling immunological synapse stability and subsequently downstream processes modulating T cell activation. In order to validate our findings mentioned above and to dissect the signaling mechanisms of the candidate + pathway in distinct CD4 T cell subsets, we propose to address following key questions: (i) How does PKCtheta/Coro1A interaction mechanistically modulate the NF-kappaB signaling pathway downstream of the T cell receptor? (ii) Does a T cell-specific coro1a knockout reveal novel functions of Coro1A in T cell biology, not identified in analyses of the conventional coro1a knockout mice? (iii) Which role play novel interaction partners of Coro1A that have been identified by an interactomics screen, in the signaling network regulating T cell responses? To achieve our goals genetic mouse models in combination with technologies from the fields of biochemistry, molecular cell biology and cellular immunology will be applied. The current project combines the expertise of the applicant, Dr. Kerstin Siegmund, in the field of T cell immunologyolerance and coronin 1A with the knowhow of the Baier laboratory in PKC signaling and is thereby set up to improve our understanding of the molecular processes of T cell activation involved in autoimmunity and inflammation in the long run.

T lymphocytes are crucial for an intact immune system. Their activation, differentiation as well as survival critically depend on molecular networks that translate external stimuli into cellular responses and thereby shape the outcome of immune reactions. However, T cell activation needs to be tightly regulated, since inappropriate T cell responses can lead to disease states such as the development of autoimmunity.The current project relies on the expertise of Dr. Kerstin Bellaire-Siegmund in the field of T cell immunology and more specifically coronin 1A and the knowledge Prof. Baiers group regarding T cell signalling and the protein kinase C theta (PKCtheta). Both molecules are important players in the signal transduction down-stream of the T cell receptor and thus activation. Deficiency for one or the other results in impaired T cell function.In our studies we could show, that coronin 1A and PKCtheta interact physically and that this interaction is of functional relevance for T cell activation. For instance, overexpression of wild-type coronin 1A impaired events down-stream of PKCtheta. Furthermore, we showed that even though coronin 1A is expressed in all leukocytes, its T cell intrinsic function is essential for T cells. Additional analyses addressing the role of PKCtheta for regulatory T cells revealed that this kinase is important for thymic development of this T cell subset; however it is dispensable for their suppressive function. Thus, targeting these molecules might provide the possibility to suppress specifically effector T cells without interfering with regulatory T cell function a strategy which would be beneficial for instance in case of autoimmunity.