c-Ski and the regulation of CD4 T cell-mediated autoimmunity and tolerance

Benaroya Research Inst At Virginia Mason, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): It is becoming clear that CD4 T cell plasticity is an important aspect of initiating and regulating immune responses. Among the factors that play a critical role in determining T cell differentiative fate is TGFß. Recent work has shown that TGFß, through its ability to induce the expression of both Foxp3 and ROR?t, is involved in iTreg/Th17 differentiation. Exposure of CD4 T cells to antigen in the presence of TGFß alone leads to iTreg development, while the presence of inflammation cytokines (e.g., IL-6) with TGFß results in Th17 differentiation. Thus, the ability of TGFß to regulate the expression of Foxp3 and ROR?t based on microenvironmental cues, is a key aspect of T cell function. Factors that regulate TGFß function are therefore important players in this process. One such factor is the proto-oncogene c-Ski. The Ski gene was first identified as v-Ski, the retroviral oncogene in Sloan-Kettering retroviruses capable of transforming chicken embryo fibroblasts. The cellular homolog, c-Ski, has been shown to be important for several aspects of embryonic development, and Ski- deficiency leads to late embryonic death. Ski functions as a natural inhibitor of the TGFß signaling pathway by targeting several downstream signaling events. However, a role for Ski in the immune system has not been determined. Given the important role of TGFß in regulating immune responses, a better understanding of Ski in the context of immune development and responses is important. For this work we have generated a mouse strain that contains a conditional knockout allele of Ski, allowing us to delete Ski specifically in T cells. These mice wll allow us to determine the role of Ski in T cell homeostasis and function. With this in mind, the aims of this proposal are: 1. Determine the role of Ski in regulating TGFß-mediated effects in CD4 T cells; 2. Determine the role of Ski in regulating T cell homeostasis; 3. Determine the effect of Ski-deficiency on CD4 T cell function.