CD11b + CD103 - Sentinel DCs Relay a Tunable Antibacterial NFκB Response in Intestinal Epithelial Cells Via TNF

Intestinal epithelial cell (IEC) NFκB signaling regulates the fine balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance, and how bacterial exposure elicits the process. Pure LPS induces epithelial NFκB activation in vivo. We found that in mice, IECs do not respond directly to LPS. Instead, CD11b+ CD103- intercrypt DCs sense LPS via TLR4 and secrete TNF to elicit epithelial NFκB signaling in their immediate neighborhood. This response is relevant also during oral enteropathogen infection. The DC-TNF-IEC axis avoids responses to luminal microbiota LPS, but enables localized or tissue-wide epithelial NFκB responses in proportion to the microbial threat. Thereby, the CD11b+ CD103- intercrypt DCs serve as important sentinels for Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows induction of defense mechanisms at an appropriate scale according to localization and intensity of microbial triggers.