Cell Biology & Genetics of T Cell Activation and Death

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): An immune response consists of a recognition phase, a phase of lymphocyte proliferation, and a phase of lymphocyte death. Most activated lymphocytes die, although a small population differentiates to become memory cells. The expansion and death phases have previously been thought to be separate aspects of cell physiology. We propose that T cell proliferation and death are coordinately regulated. Extensive evidence is provided to show that signaling pathways that are important for activation induced cell death (AICD) are also important in cytokine-induced T cell proliferation. At the same time, cytokine signaling that promotes T cell expansion, can also promote activation-induced cell death. Experiments are proposed to analyze the interactions of the FADD-caspase-8 signaling pathway and cytokine responsiveness regulated by silencer of cytokine signaling-1. We propose that a natural cycle of signaling allows cells to expand and then undergo cell autonomous AICD. The role of the FADD-caspase-8 pathway will be investigated for its contribution to homeostatic proliferation and induction of proliferation and differentiation in vivo The main tool to be created for these investigations is a conditional deletion of caspase-8. This proposal also includes experiments to investigate the role of SOCS 1 as a negative regulator of cytokine signaling in T cells. SOCS 1-/- T cells will be examined for IL-2 responses in naive, unactivated T cells. The final aim includes a proposal to examine the role of FADD and caspase-8 in regulating the levels of SOCS1 during the cycle of T cell activation, proliferation, and quiescence.