Differential usage of IL22 distal elements by innate and adaptive cells 3615

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Abstract Description Antigen-presenting cells respond to microbial insults at mucosal surfaces by producing a variety of cytokines, including IL-1b and IL-23. These specific micro-environmental cues induce the expression of “type 3” effector molecules IL-22 and IL-17 from Th17 and innate lymphoid cells (ILC3). Given the pivotal role of IL-22 in epithelial homeostasis, perturbations in its levels associate with numerous inflammatory diseases and tumorigenesis. However, the molecular mechanisms that regulate IL22 expression in distinct cell types under homeostatic or pathogenic conditions remain poorly understood. In this study we identified two distal enhancers, E22-1 and E22-2, which regulate IL22 in type 3 immune cells. Importantly, chromatin profiling revealed that E22-1 is active in both type 3 lymphoid cells, whereas E22-2 is specifically active in ILC3s. The deletion of E22-1 in mice substantially reduced IL-22 levels in different subsets of ILC3s and Th cells. A similar decrease of IL-22 in ILC3s was also observed in E22-2 KO mice but, consistent with its chromatin profiles, the deletion did not affect IL-22 production by Th cells. Further, we found that mice lacking both E22-1 and E22-2 are inefficient in clearing Citrobacter rodentium. Collectively, our findings define distinct cis-regulatory circuits for IL22 in type 3 cells, which can be exploited to design novel therapeutic strategies for IL-22 driven pathologies. Funding Sources Supported by the National Institutes of Health (NIH) grants RO1 AI134035, CA188286, AI130231, AI118852 and the Ohio State University Pelotonia Fellowship Program. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)

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