Dominant Tolerance

Random generation of antigen-specific receptors in developing lymphocytes poses a major risk of autoimmunity. Among mechanisms evolved to prevent autoimmunity regulatory T cells play a critical role. Our recent studies suggest that regulatory T cells represent a dedicated T cell lineage. Search for a genetic mechanism of regulatory T cell development and function led us to identification of Foxp3 as the regulatory T cell lineage commitment factor. We find Foxp3 expression in developing thymocytes, and therefore, regulatory T cell fate decision, depends upon increased avidity TCR-ligand interactions as well as additional factors. Our current data indicate that Foxp3 seems to be a dedicated genetic mechanism of dominant tolerance and its failure results in early onset fatal autoimmune multi-organ pathology.