Lymphotoxin Beta Receptor Signaling in Intestinal Epithelial Cells Orchestrates Innate Immune Responses against Mucosal Bacterial Infection

Epithelial cells provide the first line of defense against mucosal pathogens; however, their coordination with innate and adaptive immune cells is not well understood. Using mice with conditional gene deficiencies, we found that lymphotoxin (LT) from innate cells expressing transcription factor RORγt, but not from adaptive T and B cells, was essential for the control of mucosal C. rodentium infection. We demonstrate that the LTβR signaling was required for the regulation of the early innate response against infection. Furthermore, we have revealed that LTβR signals in gut epithelial cells and hematopoietic-derived cells coordinate to protect the host from infection. We further determined that LTβR signaling in intestinal epithelial cells was required for recruitment of neutrophils to the infection site early during infection via production of CXCL1 and CXCL2 chemokines. These results support a model wherein LT from RORγt + cells orchestrates the innate immune response against mucosal microbial infection. ► Lymphotoxin is required for early protection against mucosal C. rodentium infection ► Lymphotoxin from innate mucosal RORγt + cells is essential for protection ► LTβR on both radio-resistant and bone marrow-derived cells controls the infection ► LTβR signaling in intestinal epithelial cells recruits neutrophils for host protection