Innate Lymphoid Cells in Intestinal Homeostasis and Immune Defense – Gut_ILC

Innate immune effector cells, while exhibiting stereotyped responses in terms of rapidity and priming, have a surprising degree of functional diversity. Natural killer cells were the first ILC to be described, but more recently, it has become clear that a number of other ILC subsets exist, especially at mucosal sites. These include lymphoid tissue inducer (LTi) cells required for lymphoid tissue development, and intestinal NKp46+ ‘NK-like’ ILCs that appear to reinforce the intestinal epithelial barrier through the production of IL-22. Cytokines produced by ILCs can act on multiple cellular targets within the intestinal tract: IL-22 produced by NKp46+ cells and/or LTi cells can stimulate expression of antimicrobial peptides in intestinal epithelial cells, while IL-17 produced by LTi cells can synergize with IL-22 in the activation of epithelial cells and induce the generation and recruitment of neutrophils. IFN-g produced by classical NK cells in the gut can have pro-inflammatory effects on hematopoietic cell target, and can synergize with TNF-a to promote epithelial cell turnover and apoptosis. ILC-produced cytokines have been shown to play a critical role in intestinal defense against several pathogens including Citrobacter rodentium and Salmonella typhimurium. As ILCs are poised to modulate intestinal barrier function at several different levels, a major unresolved question concerns the specific versus redundant roles for ILCs in intestinal homeostasis and immune defense. The main aims of this project are to dissect the functional diversity of intestinal ILCs, to assess the impact of the ILC-epithelial ‘crosstalk’ in the selection of microbial flora, and to define the roles for diverse ILCs in intestinal epithelial homeostasis, in the intestinal inflammatory response and in the defense against gut pathogens.