Regulatory T cells (T-reg cells), expressing the transcription factor FOXP3, represent a distinct lineage of helper T cells indispensable for the maintenance of immune homeostasis and inhibiting autoimmune diseases. Therefore understanding the phenotype, function and regulation of this crucial T cell subset is particularly warranted to develop successful therapeutic modalities for the treatment of autoimmune pathologies. The transcriptional repressor, BCL6, regulates several critical pathways of the immune system and acts as an oncogene in B cells. BCL6 serves as a major arbiter of T cell fates, however little is known about the role of BCL6 in T-reg cells. BCL6- deficient mice (BKO mice) develop severe inflammatory disease that resembles the disease observed in mice with known T-reg defects, although the disease is primarily limited to heart and lungs. The inflammation is spontaneous, with the majority of the mice developing the disease a few weeks following birth and the mice invariably dying at an early age. The requirement for T cells in mediating the inflammation in BKO mice suggests there is an autoimmune component to the disease. Since T-reg cells are implicated in maintaining immune homeostasis by keeping effector T cell responses from causing collateral damage and keeping inflammation in check, perturbations in T-reg function offers a likely explanation for the inflammatory disease in BKO mice. Our preliminary results demonstrate elevated levels of Th2 genes and altered microRNA profiles of BKO T-reg cells that might compromise their capacity to block the heart and lung-specific inflammation. We therefore hypothesize that BCL6 has a critical role in regulating T-reg function, particularly by stabilizing the T-reg phenotype in the context of the Th2-type inflammatory setting in vivo. How this stabilization relates to the role of BCL6 in repressing Th2 gene expression in T-reg cells and its role in regulating critical microRNAs in the T-reg lineage is the focus of this proposal. INNOVATION: The concept that a key regulator of T cell differentiation regulates microRNA expression in T-reg cells is highly novel. We use innovative genetic cell- lineage marking approaches to test the role of BCL6 in T-reg cells. IMPACT: Exploring BCL6 as a novel regulatory mediator of T-reg activity can offer new insights into the molecular etiology of myocarditis and vasculitis, thus facilitating the development of new therapies targeting BCL6 for treatment of inflammation and autoimmunity. ) PUBLIC HEALTH RELEVANCE: Regulatory T cells are lineage of helper T cells indispensable for the maintenance of immune homeostasis and inhibiting autoimmune diseases. Understanding the phenotype, function and regulation of this crucial T cell subset is particularly warranted to develop successful therapeutic modalities for the treatment of autoimmune pathologies. Here we propose to study the role of the key transcriptional repressor, BCL6, in regulatory T cell function. This work will offer new insights into the molecular regulation of regulatory T cells, thus facilitating the development of new therapies targeting BCL6 for treatment of inflammation and autoimmunity. )