Role of Diet and Commensal Microbiome in Recruitment and Functional Differentiation of CD8 T cells in the Small Intestinal Epithelium

Abstract

Intestinal intraepithelial lymphocytes (IELs) consist of tissue resident TCR and - T lymphocytes, which display immediate effector function. The TCR+ population contains an innate self-specific CD8+ subset and a major subpopulation of mainstream CD8+ T cells that migrate there before any pathogen-encounter. How CD8+ T cells are generated as pre-existing fully differentiated protective cells is poorly understood. Here, we show that at steady state, CD8+ IELs depend on dietary antigens (Ags) for their recruitment to the small intestine epithelium and functional maturation. They also require commensal microbiota in this process. Unlike pathogen-induced memory CD8+ T cells, dietary Ag-induced CD8+ IELs require continuous exposure to their cognate dietary Ags for their protective capacity. Amongst various dietary components, including wheat, corn, soybean and yeast, commensal bacteria are prerequisite for the early development of wheat-induced CD8+ IELs. Particulary, commensal microbiota is required at the weaning stage, and colonization at later time points are highly inefficient. Mechanistically, the generation of diet-induced CD8+ IELs depends on T-BET but not on IL-15. Instead, IL-12 family members, IL-27 and IL-12 play differential roles in the recruitment and functional differentiation of CD8+ IELs at steady state. Notably, mice lacking diet-induced T cells in the intestinal epithelium have significantly decreased immunity against an oral infection with Listeria monocytogenes. Collectively, the data show that dietary Ags are critical for the generation of protective T cells that are pre-existing at the mucosal border prior to pathogen challenge and early exposure to commensal bacteria is important for the proper development of dietary Ag dependent immune repertoire in the gut.