A long standing, but poorly understood observation in immunology is the link between homeostatic proliferation and autoimmune diseases. Recent studies on homeostatic proliferation of T cells in a lymphopenic environment and on lymphopenia associated with autoimmune diseases have led to a novel hypothesis that homeostatic proliferation of T cells is a major contributing factor in the development of autoimmune diseases. However, a lack of genetic models for the checkpoint of homeostatic proliferation in the mouse has made it difficult to causatively link homeostatic proliferation to autoimmune diseases. My laboratory has recently made two observations that may help to bridge this gap. First, we observed a robust lymphoproliferation and an interesting transition from homeostatic to antigen-driven proliferation in the Scurfy mice during the perinatal period. Secondly, we demonstrated that expression of CD24 in the T cells is essential for their homeostatic proliferation in the lymphopenic host. These two genetic models provide us with exciting possibilities that causatively link homeostatic proliferation and autoimmune disease. In addition, our analysis of regulation and ligands for CD24 may allow us to reveal the molecular mechanism by which CD24 mediates IPEX (immunodeficiency, polyadenopathy, enteropathy, X-linked) pathogenesis. We will first test whether inhibition of homeostatic proliferation by target mutation of CD24 can ameliorate the development of autoimmune diseases in the Scurfy mice. We will also test the idea that CD24 is a direct target for transciptional repression and/or activation by FoxPS and that mutation of FoxPS will result in over- expression of CD24 on T cells and perhaps down regulation of APC, either or both of which contributed to exacerbated homeostatic proliferation. Our proposal will not only reveal the critical linkage between lymphoproliferation, but it may also establish a novel molecular checkpoint for homeostatic proliferation and autoimmune diseases. Targeting this checkpoint may provide a novel therapeutic approach for autoimmune diseases that involve abnormal homeostatic proliferation. ? ? ?
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