Crucial Role of Lymphotoxin Produced by ILC3 in the Development of Intestinal Adaptive Immune Responses and Autoimmunity

Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Induction of proper intestinal adaptive immune responses in the gut upon colonization of the gut with commensals ensures protection against invading pathogens, maintenance of epithelial barrier integrity and control of microbiota.   However, mechanisms governing these responses still remain poorly defined. Here we report critical function of surface LTα₁β₂ expressed by RORγt⁺ innate lymphoid cells (ILC3) in controlling intestinal B and T cells in the absence of gut-associated lymphoid tissue (GALT). First of all, ILC3-derived LTα₁β₂ is crucial for IL-6, IL-12 and IL-23 production by gut dendritic cells in naive state and during inflammation, resulting in defective production of IL-22 from T lymphocytes and ILC3s. Next, surface LTα₁β₂ produced by RORγt⁺ ILC controls T cell-independent IgA induction in the small intestine, resulting in the exclusive T cell-dependent IgA plasma cells induction in the gut. IgA produced by plasma cells from mice lacking LTα₁β₂ expression on ILC3 exhibits enhanced reactivity to the commensal microbiota, leading to altered microbiota composition. Finally, LTα1β2 produced by ILC3 prevents development of autoantibodies via microbiota-dependent mechanism. Altogether, these data ascribe novel essential function for membrane-bound lymphotoxins produced by ILC3 in organizing adaptive immune responses in the gut, in the control of the commensal microbiota and subsequent development of autoimmunity.