APCs and environmental cues for inflammation-linked Th17 immunity

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Summary of Work Understanding how antigen presenting cells (APCs) use environmental cues to influence T cell antigen specificity and function is a pressing issue since IL-17-producing CD4 T cells (Th17) can exist in two dichotomous states: 1) Th17 that exist in health and cause no inflammation (“Th17h”) and 2) Th17 that expand during autoimmune and inflammatory disease (“Th17i”). Because some tissues, like small intestine, naturally contain large numbers of Th17h cells, distinguishing Th17h and Th17i cells in these tissues has been a remarkable challenge. Consequentially, the origins, functions and even the existence of Th17i cells in these tissues have been highly debated. To begin to resolve this we took a focused look at Th17 cells in inflamed small intestine and identified populations of Th17i cells readily distinguishable from Th17h cells since these Th17i cells have distinct antigen specificity and localization than do Th17h cells. By all measures thus far these Th17i cells are exclusive to inflammation and do not appear to exist in conditions of health. With our new approach to distinguish Th17h and Th17i cells, the objective of this proposal is to understand the nature and origins of Th17i cells, and the environmental cues and APCs underpinning their expansion in inflammation.