TLRs in Host Commensal Interactions

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DESCRIPTION (provided by applicant): Inflammatory Bowel Diseases are characterized by disregulated immune responses in the intestine. The mechanisms responsible for the induction of pathogenic T cell responses are still poorly defined, although the recent progress has highlighted the critical roles of commensal bacteria, the innate immune system, myeloid cells (dendritic cells (DC) and macrophages), TH17 cells and regulatory T cells (Tregs). These recent findings have brought up a new focus of investigation, including characterization of the key innate immune signaling pathways and their roles in the development of pathogenic T cell responses. In particular, analyses of TH17 responses in the intestine have elucidated both pathogenic and protective roles of cytokines produced by these cells in the development of colitis. Similarly, accumulating evidence indicates that different innate signaling pathways (for example, IL-23-driven, versus TGFb and IL-6-driven) may have differential roles in the generation of pathogenic versus non-pathogenic or protective Th17 responses. In this proposal, we will investigate the role of innate immune sensing pathways in the initiation of pathogenic T cell responses in the intestine. Specifically, we will investigate the role of IL-6, IL-1, and TGFb in the generation of TH1 and TH17 responses, and their role in development of colitis. We will also examine the role of different innate pathways that lead to the generation of TH17 responses in the intestine.