B cells produce IL-27 to interact with types 3 innate lymphoid cells and mediate the formation of lymphoid follicles for IgA production and inflammation resolution in the gut 4035

Abstract Description B cells produce IgA to maintain gut homeostasis. As shown by us, they also produce pleiotropic cytokine IL-27 to regulate the antibody response. These, together with the link of the IL27 gene polymorphisms that reduce IL-27 expression to the early-onset of inflammatory bowel disease (IBD), prompted us to investigate the role of B cell-produced IL-27 in colitis. Here we showed that B cells upregulated IL-27 expression in most isolated lymphoid follicles (ILFs) in IBD patients and in gut lymphoid tissues in a murine model of colitis, i.e., after treatment of dextran sulfate sodium (DSS). Mice with B cell-specific deficiency in IL-27 were impaired in IgA production and inflammation resolution, in association with a decreased proportion of ILC3s that expressed IL-22. Accordingly, deficiency of IL-27 receptor in ILC3s, but not T cells, resulted in increased colitis symptoms. Conversely, B cells programmed in vitro to produce IL-27, when administered to DSS-treated C57 mice, could reduce colonic inflammation and re-normalize the altered immune landscape. Such “therapeutic effects” depended on the interaction of IL-27+ B cells with IL-27 receptor-expressing ILC3s within ILFs, whose formation was enhanced. Finally, B cells could be induced to produce IL-27 after being primed with cGAMP in a STING-dependent manner. Overall, B cells maintained intestinal homeostasis by interacting with ILC3s and promoting ILF formation and could be explored as cell-based therapeutics for IBD. Funding Sources Supported by NIH/NIAID R21 AI135599-02; NIH/NIAID R01 AI153506-A1; Crohn’s & Colitis Foundation Senior Research Award Topic Categories Mucosal and Regional Immunology (MUC)