Regulation of CD8+ T Cell Homeostatis by IL-4

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This proposal will study IL-4 regulation of T cell homeostasis and immunity. It will investigate the four part hypothesis that: 1) IL-4 stimulates CD8+ T cells to proliferate; 2) IL-4 also stimulates non-T cells to differentiate into regulatory cells that suppress activated CD8+ T cells; 3) differences in the kinetics of these two processes cause IL-4 to first enhance, then suppress CD8+ T cell responses; and 4) these phenomena are important in CD8+ T cell homeostasis in health and disease. This hypothesis is based on in vivo mouse studies that demonstrate that: 1) IL-4 is essential for normal CD8+ T cell homeostasis, especially memory CD8+ T cell homeostasis; and 2) physiological concentrations of IL-4 acutely induce CD8+ T cells to proliferate through a partially Stat6-dependent process but more slowly decrease CD8+ T cell responses and cell number through an entirely Stat6-dependent process. Suppression is associated with the appearance of an enlarged, activated population of CD11b+Ly6Ghi neutrophils, which have been implicated by other investigators in the inactivation and killing of activated CD8+ T cells. Our hypothesis is addressed in 3 specific aims. The first evaluates signaling requirements for IL-4 stimulation of T cell activation and survival. It will determine the importance of IL-4 activation of Stat6, Stat5, and PI-3K for the mitogenic and anti-apoptotic effects of IL-4. It will also investigate why both IL-4 and IL-15 are required to maintain memory CD8+ T cells. The second aim addresses IL-4-activation of regulatory cells. It will identify and characterize the spleen cells activated by IL-4 to suppress and kill activated CD8+ T cells; determine the dose of IL-4 required to activate these regulatory cells; identify the signaling pathways important for their activation; identify the mechanism(s) by which they kill activated T cells, and evaluate their importance in a mouse model in which IL-4 suppresses cytotoxic graft vs. host disease (GVHD). The third aim will evaluate the effects of endogenously-produced IL-4 and a related cytokine, IL-13, on CD8+ T cell homeostasis in health and disease. To allow evaluation of the generalizability of our results, this aim will examine the effects of IL-4 and IL-13 on T cell homeostatsis in mouse models of two inflammatory disorders: allergic airway inflammation (asthma) and Omann's syndrome; and mouse models of three infectious diseases: schistosomiasis, malaria, and lymphocytic choriomeningitis virus (LCMV) infection. Each of these models has been chosen because it can provide some unique information about IL-4 regulation of T cell homeostasis and immunity and because it also can shed light on the disease-relevance of IL-4 regulation. Proposed experiments will be performed in vivo and use transgenic mice, recombinant cytokines, monoclonal antibodies, cell transfer systems, CFSE labeling, BrdU incorporation, assays of in vivo cytokine production and flow cytometry to test our hypothesis. Results of these studies should identify the circumstances in which IL-4 promotes or regulates CD8+ T cell responses and provide a guide to the potential uses of IL-4 and IL-4 antagonists for amplifying or suppressing adaptive or maladaptive CD8+ T cell responses in humans.