DEATH RECEPTOR SIGNALING PATHWAYS IN T CELL DEVELOPMENT

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The goal of my research is to elucidate the roles of apoptotic signaling pathways in the development and homeostasis of T cells. Toward this goal, I have produced transgenic mice in which specific components of these pathways have been blocked. In one transgenic line, a dominant-negative form of an adapter molecule known as FADD is expressed in developing thymocytes and mature T lymphocytes. FADD has been shown to mediate apoptotic signaling following ligation of certain nerve growth factor-/tumor necrosis factor-receptor family members. A dominant negative mutant of FADD (FADDdd) interferes with death induction following triggering of these receptors. Surprisingly, FADDdd transgenic T cells appear to undergo normal apoptosis in the thymus, but have defective development and reduced proliferation in response to antigenic stimulation. These paradoxical results suggest that the same mechanisms that control death also control survival and proliferation. Additionally, my research has demonstrated that this control is exerted at the level of the cytokine receptor/Jak/Stat pathway. The research outlined here will attempt to determine the molecular nature of this process in T cell development and homeostasis and to more broadly determine the interplay between death- and cytokine-receptor pathways.