Humans with mutations in the foxpS gene suffer from a complex of autoimmune disorders (IPEX) that results from the lack of regulatory T lymphocytes, and leads to the eventual death of these patients in childhood. Recent studies in experimental models have established that FoxpS, which is a member of the forkhead family of DMA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function, and therefore is crucial for acquired immune tolerance. Expression of FoxpS by T lymphocytes leads to the induction of genes associated with tolerance, and to the repression of genes that cause inflammation and immune pathology. The mechanisms by which FoxpS induces this genetic program, however, are not known. Regulatory T cells are also thought to be crucial for the inhibition of alloimmune responses during organ transplantation, and have been implicated in the control of autoimmune disease. An important goal in the treatment of patients with autoimmune disorders or organ transplants is to induce immunologic tolerance, and a basic understanding of the mechanisms that underly this process will likely be a prerequisite for the successful clinical treatment of these diseases. The studies proposed in this application are centered around basic questions of FoxpS transcriptional biology, and will add significantly to our understanding of how FoxpS regulates gene expression and promotes tolerance. A central tenet of these studies is that the regions of FoxpS mutated in IPEX patients are required for basic aspects of FoxpS function, and the studies herein are designed to determine these functions. The information gained from these studies will likewise lead to novel therapeutic strategies by which tolerance can be promoted in patients with autoimmune disease and organ transplants.