Maintenance of mucosal homeostasis by commensal Th17 cells

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Mucosa are sites of conventional immune system attack for defense against invasive pathogens. Mucosa were also once regarded simply as inert barriers preventing commensal microbes from accessing sterile tissues. Instead, emerging evidence suggests a complex interplay between commensal microbes, barrier epithelial cells, and the immune system that is essential for local and systemic homeostasis of the host. We have recently provided insight into how recognition of commensal components by epithelial and innate immune cells triggers a specific immune reaction and why the nature of this reaction could foster host- microbe symbiosis instead of outright microbial rejection. Specifically, we showed that antigen acquisition be intestinal epithelial cells (IECs) of commensal antigens drives a non-pathogenic commensal Th17 cell response. Here we propose to mechanistically examine the fate of intracellular IEC antigens and the role of IECs in the process, as well as the phenotype and function of the generated Th17 cells. We will address these mechanism by pursuing two specific aims to explore 1) Role of IECs in priming of commensal T cell responses and 2) Generation and function of anti-inflammatory commensal Th17 cells. Our studies address fundamental mechanisms of mucosal immunity to commensal microbes and if successful will provide novel mechanisms of IEC function, as well as pathways for generation of protective mucosal T cell responses.