An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses

Teruyuki Sano, Wend Huang, Jason A. Hall, Yi Yang, Alessandra Chen, Samuel J. Gavzy, June-Yong Lee, Joshua W. Ziel, Emily R. Miraldi, Ana I. Damingos, Richard Bonneau and Dan R. Littman.

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RORγt+ Th17 cells are important for mucosal defenses, but also contribute to autoimmune disease. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. Elucidation of the molecular and cellular requirements for SFB-induced Th17 cell differentiation may provide insight into pathogenesis of human inflammatory diseases. In this report, we describe a two-step process for the functional differentiation of intestinal Th17 cells following colonization of mice with SFB.  The first step is the priming and polarization of antigen-specific CD4+ T cells in the tissue-draining lymph nodes, resulting in a poised state marked by the expression of RORγt, and the second is the activation of a cytokine gene expression program in a tissue microenvironment in which epithelial cell-derived factors SAA1 and SAA2 act on poised cells. We identified an unexpected SFB-dependent role of type 3 innate lymphoid cells (ILC3), which responded to IL-23 by secreting IL-22 that, in turn, induced epithelial SAA production in a Stat3-dependent manner. These findings highlight the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.

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