γδ intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface

The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. Here we show that gamma delta intraepithelial lymphocytes (gamma delta IEL) of the small intestine produce innate antimicrobial factors in response to resident bacterial "pathobionts" that penetrate the intestinal epithelium. gamma delta IEL activation was dependent on epithelial cell-intrinsic MyD88, suggesting that epithelial cells supply microbe-dependent cues to gamma delta IEL. Finally, gamma delta T cells protect against invasion of intestinal tissues by resident bacteria specifically during the first few hours after bacterial encounter, indicating that gamma delta IEL occupy a unique temporal niche among intestinal immune defenses. Thus, gamma delta IEL detect the presence of invading bacteria through cross-talk with neighboring epithelial cells and are an essential component of the hierarchy of immune defenses that maintain homeostasis with the intestinal microbiota.