Trapping Grb2 within immune cells: The role of transmembrane adaptor proteins

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SIT is a recently discovered transmembrane adaptor molecule that represents a regulator of signals emanating from the T cell receptor. Previous work from our laboratory has shown that, depending on its phosphorylation status, SIT can act as a positive or a negative signaling element of T-cell activation in Jurkat T cells. To further extend the studies on the function of SIT and to assess its role in vivo we have produced SIT knock-out mice. SIT deficient mice exhibit a defect in the development of ab-T cells and show a 2-3 fold higher number of gd-T-lymphocytes in the peripheral lymphoid organs. The aim of this project is to investigate the mechanisms by which SIT can affect development and homing of T lymphocytes, as well as its function in B-lymphocytes and plasma-cells, which has yet to be investigated. Mice lacking SIT will be used to dissect (i) thymic selection processes (positive and negative selection in a TCR transgenic background) and (ii) intracellular biochemical cascades after the triggering the T-cell receptor in thymocytes. In addition to the evaluation of the differentiation potential of T-cells, we will focus our investigation on the function of peripheral T-, B- and plasma cells (proliferation, immune response and homing). Finally, we will develop additional animal models (SIT transgenic mice, SIT/TRIM double knock-out mice) to further expand our study of SIT function.