Resident intestinal dendritic cells - negative regulators of colitis

Overall Objectives. Resident DCs play important· roles in preventing inflammatory responses in the intestinal tract, in part by promoting development of more Tregs. We have shown that deletion of resident DCs increases susceptibility to DSS colitis [1, 2], demonstrating a protective role for resident intOCs. Functional plasticity by DCs raises the possibility that these cells can be made anti-inflammatory. However, understanding mechanisms regulating immunosuppressive functions of intOCs is critical. We show that PPARy has an important role in maintaining an immunosuppressive and tolerogenic phenotype in mouse intDCs. Using a novel conditional deletion mouse strain developed in our lab, we will test the hypothesis that PPARy functions as a master regulator of immune function in intOCs and that reduced expression and/or function of PPARy in DCs increases susceptibility to colitis. We will determine if similar changes in PPARy occur in intOCs from patients with IBD and whether DCs from IBD patients maintain responsiveness to activated PPARy. Finally, we will delineate molecular changes in PPARy protein that occur in intOCs during colitis. Understanding how PPARy levels and activity are altered in intOCs during colitis may lead to novel targeted therapeutic approaches for IBD.