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

Abstract

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 LTβR 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.To define the role of LT in IBD, we analyzed the expression of LTα and LTβ 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.We found that LTα and LTβ expression was increased in inflamed versus uninflamed colon tissue of Crohn's disease pediatric patients. We further found that LTα and LTβ 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 LTβ 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 LTα and LTβ 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 LTβR 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.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.