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Characterization of the role of p59Fyn in T cell development and anergy Utting, Oliver B.

Abstract

Signaling via the T cell receptor (TCR) is essential for the development of thymocytes and the mounting of peripheral T cell responses. Studies of proximal TCR signaling have demonstrated that two kinases, Lck and Fyn, are involved in the initial TCR phosphorylation events that eventually lead to T cell activation. Studies of these two kinases generally point to Lck having a major role in TCR signaling and to Fyn playing a secondary, perhaps redundant role. In this thesis I have investigated the hypothesis that the role Fyn plays in T cell signaling is not redundant, and that Fyn is important for both thymocyte selection and peripheral T cell responses. Using transgenic mice that express TCRs with different affinities for their ligands, I have found that Fyn plays an important role in thymocyte selection and that Fyn is required for T cell responses to low affinity ligands. T cell anergy is an important form of T cell tolerance. Fyn has often been implicated in T cell anergy, but the requirement for Fyn in this phenomenon is still unclear. I have characterized a model for in vivo induced T cell anergy that involves a mature CD4⁻CD8⁻ αβTCR⁺ population of peripheral T cells. Using this model system, I found that deletion of Fyn led to a partial recovery from the proliferation defect observed in anergic cells. These anergic cells also have an enhanced ability to survive in vitro. Enhanced survival of anergic cells was dependent on signaling through elevated expression of IL-2Rβ in a Fyn-dependent manner. It appears that Fyn plays unique roles in the induction of T cell anergy and the survival of anergic T cells. Biochemical characterization of anergic T cells revealed signaling defects associated with incomplete phosphorylation of TCR-ζ, a failure to phosphorylate ZAP-70 and LAT, and a failure to mobilize intracellular calcium. Signaling via the Ras pathway is completely intact in these cells, and they have a lowered triggering threshold for activation and hyperproliferate if exogenous IL-2 is added. These unique properties of this population of anergic T cells indicate that these cells may be re-activated by bystander immune responses.

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