Lymphotoxin Controls the IL-22 Protection Pathway in Gut Innate Lymphoid Cells during Mucosal Pathogen Challenge

摘要

Innate lymphoid cells (ILCs) have emerged as important players, regulating the balance between protective immunity and immunopathology at mucosal surfaces. However, mechanisms that regulate ILCs' effector functions during mucosal pathogenic challenge are poorly defined. Using mice infected with the natural mouse enteric pathogen Citrobacter rodentium, we demonstrate that lymphotoxin (LT) is essential for IL-22 production by intestinal ILCs. Blocking of LT beta R signaling dramatically reduced intestinal IL-22 production after C. rodentium infection. Conversely, stimulating LT beta R signaling induced an IL-22 protection pathway in LT-deficient mice. Furthermore, exogenous IL-22 expression rescued LT beta R-deficient mice. IL-22-producing ILCs were predominantly located in lymphoid follicles in the colon and interacted closely with dendritic cells (DCs). We find that an LT-driven positive feedback loop controls IL-22 production by ROR gamma t(+) ILCs via LT beta R signaling in DCs. Taken together, our data show that LT beta R signaling in gut lymphoid follicles regulates IL-22 production by ILCs in response to mucosal pathogen challenge.