Mucosal surfaces such as the intestinal epithelium provide a complex challenge to the immune system, as they must maintain effective immunity against potential pathogen attack while also tolerating commensal microrganisms and dietary antigens. The balance between tolerance and immunity is mediated in large part by the specialized T cell populations, regulatory T cells (Tregs) and Th17 cells. Disruption of the balance between these subsets has been heavily implicated in causing colitis through studies in both mice and humans. Furthermore, Th17 cells are emerging as contributors to many other inflammatory and autoimmune disorders. Understanding how Th17 responses are initiated and regulated is therefore critical to our understanding of both intestinal immunity and chronic inflammatory disease. We are interested in the how Dendritic Cells (DCs) and other antigen presenting cells initiate and maintain the correct balance of T-helper cell subsets. Our long term goal is to understand how DCs distinguish normal from inflamed tissue and orchestrate appropriate immune responses. We have recently shown that T cell responses to TGF- , which is essential for Th17 cell development, requires activation of latent TGF- mediated by a? integrins on DCs. Deletion of either 1v or the partner 8 chain in myeloid cells causes loss of both Th17 cells and Tregs in the intestine, leading to colitis. We hypothesize that DC expression of a? 8 and subsequent activation of TGF- controls induction and maintenance of Th17 responses. In this grant we propose to understand how av28 is regulated in DCs during Th17 responses. Using a?-conditional knockout mice we will test whether DC a? integrins are required for host defense against intestinal infections and for preventing Th17-mediated inflammatory disease. We will define the signals that regulate expression of a? 8 in intestinal DCs and use cell biology and biochemical approaches to understand how a? 8?-mediated TGF- activation is regulated. Completion of the proposed aims will provide a much needed understanding of how DCs promote the initiation of Th17 cells in the intestine and regulate their subsequent differentiation in response to environmental and infectious challenges.

Public Health Relevance

Immune responses at mucosal sites such as the intestine are tightly regulated to prevent reactions to commensal bacteria but maintain protective immunity. Breakdown in this regulation has been linked to many inflammatory diseases; including inflammatory bowel disease. The cytokine TGF-? plays a major role in this regulation and the goal of this project is to understand how TGF-? activity is locally regulated by the immune system to generate protective immunity but prevent inflammation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Grey, Michael J
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Benaroya Research Institute at Virginia Mason
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