Modulation of T Cell Activation and Tolerance by DRAK2

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Although immune tolerance is clearly important for the prevention of autoimmunity and the maintenance of lymphocyte homeostasis, suprisingly little is known about the intracellular signaling pathways that are involved. To this end, we have identified DRAK2, a serine/threonine kinase that is highly enriched in lymphoid tissues. As a member of the DAP family of kinases, DRAK2 induces apoptosis upon ectopic expression in certain cell lines. In mice with an engineered deficiency in DRAK2, a number of important defects in T lymphocyte development and activation are apparent. T cells derived from these mice are hyperproliferative to suboptimal stimulation through the T cell receptor, indicating an unexpected role in T cell quiescence for this kinase. In accord with this finding, DRAK2-/- mice have an increased proportion of activated T cells in peripheral lymphoid organs. Furthermore, DRAK2-deficient T cells proliferate in the absence of costimulatory signals normally required for T cell activation. We have found that whereas wildtype T cells require crosslinking of both the T cell receptor (TCR) and CD28 for a rapid and sustained calcium response, DRAK2-deficient T cells require only stimulation via the TCR. Paradoxically, clonal expansion following superantigen exposure is dramatically defective in DRAK2-deficient T cells. This defective responsiveness to superantigen is due to enhanced activation-induced cell death (AICD). We are curious about the mechanisms by which DRAK2 interferes with T cell activation and how its activity may modulate immune tolerance. We will determine if known T cell activation pathways are defective in DRAK2-/- mice. We will characterize the kinase biochemically to determine its mode of action. Finally, we will assess the consequences of its absence when AICD is blocked. These results are aimed at providing a more thorough understanding of negative regulation of T cell activation, and how such negative regulation contributes to immune tolerance.