Humans with mutations in the foxpS gene suffer from a complex of autoimmune disorders (IPEX) thatresults from the lack of regulatory T lymphocytes, and leads to the eventual death of these patients inchildhood. Recent studies in experimental models have established that FoxpS, which is a member of theforkhead family of DMA binding proteins, is necessary and sufficient for specification of regulatory Tlymphocyte lineage choice and function, and therefore is crucial for acquired immune tolerance. Expressionof FoxpS by T lymphocytes leads to the induction of genes associated with tolerance, and to the repressionof genes that cause inflammation and immune pathology. The mechanisms by which FoxpS induces thisgenetic program, however, are not known. Regulatory T cells are also thought to be crucial for the inhibitionof alloimmune responses during organ transplantation, and have been implicated in the control ofautoimmune disease. An important goal in the treatment of patients with autoimmune disorders or organtransplants is to induce immunologic tolerance, and a basic understanding of the mechanisms that underlythis process will likely be a prerequisite for the successful clinical treatment of these diseases. The studiesproposed in this application are centered around basic questions of FoxpS transcriptional biology, and willadd significantly to our understanding of how FoxpS regulates gene expression and promotes tolerance. Acentral tenet of these studies is that the regions of FoxpS mutated in IPEX patients are required for basicaspects of FoxpS function, and the studies herein are designed to determine these functions. Theinformation gained from these studies will likewise lead to novel therapeutic strategies by which tolerancecan be promoted in patients with autoimmune disease and organ transplants.
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