Research ArticleINNATE LYMPHOID CELLS

IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s during colitis

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Science Immunology  24 Apr 2020:
Vol. 5, Issue 46, eaav1080
DOI: 10.1126/sciimmunol.aav1080

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Drivers of IL-22 secretion by ILC3s

Secretion of the cytokine interleukin-22 (IL-22) by innate lymphoid cells and intestinal T cells in the gut promotes epithelial integrity and provides protection against intestinal pathogens. Bauché et al. examined which cytokines and signal transducer and activator of transcription (STAT) proteins activate IL-22 production by group 3 innate lymphoid cells (ILC3s) in mice. They found that IL-2 acting through STAT5 contributed to the induction of IL-22 in ILC3s, bolstering the ability of T cell–deficient mice to fend off Citrobacter rodentium infection. IL-23 activated both STAT3 and STAT5 in ILC3s, enabling binding of a STAT3/STAT5 complex to the IL-22 promoter. These studies revealed that ILC3s and T cells use distinct sets of cytokines and STATs to achieve activation of IL-22 expression.

Abstract

Signal transducer and activator of transcription (STAT) proteins have critical roles in the development and function of immune cells. STAT signaling is often dysregulated in patients with inflammatory bowel disease (IBD), suggesting the importance of STAT regulation during the disease process. Moreover, genetic alterations in STAT3 and STAT5 (e.g., deletions, mutations, and single-nucleotide polymorphisms) are associated with an increased risk for IBD. In this study, we elucidated the precise roles of STAT5 signaling in group 3 innate lymphoid cells (ILC3s), a key subset of immune cells involved in the maintenance of gut barrier integrity. We show that mice lacking either STAT5a or STAT5b are more susceptible to Citrobacter rodentium–mediated colitis and that interleukin-2 (IL-2)– and IL-23–induced STAT5 drives IL-22 production in both mouse and human colonic lamina propria ILC3s. Mechanistically, IL-23 induces a STAT3-STAT5 complex that binds IL-22 promoter DNA elements in ILC3s. Our data suggest that STAT5a/b signaling in ILC3s maintains gut epithelial integrity during pathogen-induced intestinal disease.

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