TRUSTEES OF INDIANA UNIVERSITY
Allergic diseases, such as asthma, are promoted by abnormal differentiation of T helper type 2 (Th2) cells. A recently described T cell subset (termed "Th17" cells) has been found to promote inflammation and autoimmune disease, in large part due to their secretion of the cytokine IL-17. An important goal for the management of T cell-mediated diseases is to achieve a complete understanding of the regulatory mechanisms controlling the differentiation of Th2 and Th17 cell types. The BCL-6 gene, originally identified as an oncogene for B cell lymphoma, encodes a transcriptional repressor protein. We have shown previously that BCL-6 is a potent inhibitor of Th2 cell differentiation, and BCL-6-deficient mice develop greatly exaggerated Th2 responses and Th2-type inflammation. We have recently found that BCL-6-deficient T cells are severely impaired in their ability to undergo Th17 differentiation, indicating that BCL-6 function is required for normal Th17 differentiation. The cytokine IL-6 can promote Th17 differentiation, but the Th2 cytokine IL-4 strongly blocks Th17 differentiation. We have found that BCL-6 is necessary to repress IL-4 expression induced by IL-6 during Th17 differentiation. Further, we have found that BCL-6 is up-regulated in T cells stimulated under Th17 conditions, indicating a unique requirement for BCL-6 in Th17 differentiation. Our hypothesis is that BCL-6 is critically required for Th17 responses because BCL-6 represses IL-6-induced IL-4 and/or IL-4 signals that can block Th17 differentiation. We will test this hypothesis with four specific aims outlined below. The lethal Th2-type inflammatory disease that develops in BCL-6-deficient mice underscores the critical role of BCL-6 in T cell differentiation. Elucidating the molecular details of the role of BCL-6 in the Th2 and Th17 pathways will increase our understanding of how T helper cell differentiation is regulated and should promote the development of new drug targets for the treatment of human allergic and autoimmune diseases. Further, since BCL-6 is a major oncogene in human B cell lymphoma, increased knowledge of BCL-6 function will enhance our general understanding and treatment of B cell lymphoma.