Transforming growth factor-beta (TGF-b) plays a critical role in maintaining gut immune homeostasis. Although ubiquitously expressed, TGF-b must be activated in order to enable subsequent signaling. TGF-b activation thus represents a major point of regulation of intestinal immune responses.I have shown that expression of alpha-v-beta-8 integrin (avb8) by dendritic cells (DCs) is required to activate TGF-b so that it can signal to T cells. Furthermore, I have shown that avb8 expression is restricted to intestinal CD103+ DCs. However the mechanisms by which avb8 expression, and thus the ability to activate TGF-b, is restricted to this subset of DCs are unknown.In this fellowship, I propose (1) to define the mechanisms by which avb8 expression is regulated in DCs, and (2) to determine whether avb8 expression program can be manipulated in order to control intestinal inflammation.These studies will provide a detailed understanding of how DCs acquire a key immune-regulatory function, the activation of TGF-b. Furthermore, they will explore whether this is disrupted in patients with Inflammatory Bowel Diseases (IBD) and if avb8 expression can be manipulated in DCs. Together, this will provide new information on how intestinal homeostasis is established, and open new areas of research for the development of IBD treatment.The increase in IBD and the chronic and debilitating nature of these disorders emphasize the relevance of a better understanding of the processes that underlie normal regulation of mucosal immune responses. The implementation of this proposal will build on both the expertise of the Host Institution and the transfer of unique know how and tools by the Applicant from Harvard Medical School. This transfer includes both reagents and collaborations I developed during my postdoctoral experience. Thus this proposal will develop long-lasting cooperation between leading US-Research center and contribute to increasing European excellence and competitiveness.