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O-009 Lymphotoxin Links Microbiota and Group 3 Innate Lymphoid Cells to Protect Against Intestinal Inflammation

Background:The balance between immune defense and inflammation in the gut is a highly regulated process that requires interactions between intestinal epithelial cells and the underlying immune system. RORgt+ group 3 innate lymphoid cells (ILC3s) have emerged as important regulators of intestinal inflammation. However, the signals that control the function of ILC3s are poorly understood. Recent studies revealed lymphotoxin (LT), a member of TNF family cytokines, as a novel regulator of ILC3s. These studies suggest that interaction of surface LT on ILC3s with LT&bgr;R on intestinal epithelial cells, and mononuclear phagocytes is required for IL-22 production and protection against mucosal damage. However, the upstream mechanisms regulating LT expression during mucosal damage remain largely unknown. Methods:To define the role of LT in IBD, we analyzed the expression of LT&agr; and LT&bgr; in inflamed and uninflamed colon tissue biopsies of Crohn disease pediatric patients by real-time PCR. Additionally, mouse models of intestinal inflammation induced by mucosal bacterial pathogen Citrobacter rodentium or dextran sulfate sodium (DSS) administration were used. Results:We found that LT&agr; and LT&bgr; expression was increased in inflamed versus uninflamed colon tissue of Crohn's disease pediatric patients. We further found that LT&agr; and LT&bgr; expression was rapidly induced in the colon during C. rodentium-induced colitis or DSS administration preceding upregulation of IL-22. LT expression by ILC3 was critical for epithelial protection because mice lacking LT&bgr; in ILC3s failed to induce IL-22 during epithelial damage following DSS administration and displayed increased body weight loss, severe colon inflammation and reduced survival. Antibiotic treatment prevented LT&agr; and LT&bgr; upregulation in the colon during epithelial damage induced by DSS suggesting that sensing of commensal microbiota is necessary for induction of LT. Consistently, MyD88-deficient mice failed to upregulate LT expression in colon, displayed reduced ILC3s numbers and IL-22 production in colon in C. rodentium and DSS-induced colitis models. Further, stimulation of LT&bgr;R signaling with an agonistic antibody rescued ILC3s numbers and IL-22 production in the colon and protected MyD88-deficient mice from intestinal inflammation indicating that LT pathway is regulated by MyD88 signaling. Conclusions:These results suggest that signals from the commensal microbiota or mucosal pathogens activate a MyD88-dependent mechanism for LT upregulation, ILC3s recruitment and IL-22-mediated protection against intestinal inflammation. Thus, manipulation of LT signaling may represent a novel therapeutic pathway to limit epithelial damage and promote mucosal healing.