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 ROR gamma t, but not from adaptive T and B cells, was essential for the control of mucosal C. rodentium infection. We demonstrate that the LT beta R signaling was required for the regulation of the early innate response against infection. Furthermore, we have revealed that LT beta R signals in gut epithelial cells and hematopoietic-derived cells coordinate to protect the host from infection. We further determined that LT beta R 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 ROR gamma t(+) cells orchestrates the innate immune response against mucosal microbial infection.