Dietary antigens drive the generation of functional cytotoxic intraepithelial lymphocytes for early defense against foodborne pathogens

Intraepithelial lymphocytes (IELs) constitute the largest lymphocyte population in the body and exhibit direct cytotoxic effector functions. How IELs are generated and maintained as effector T cells, however, is poorly understood. While significant attention has been given to the role of commensal microbiota in the intestine, the predominance of dietary components in the small intestine suggests that dietary antigens may regulate IEL generation and homeostasis. Here, we show that conventional TCRab + CD4 + and CD8 + IEL populations are present in normal numbers in germ-free (GF) mice which lack microbiota.However, these IELs are severely depleted in antigen-free (AF) mice, GF mice fed an amino acid diet devoid of proteins. Moreover, the few remaining IELs in AF mice lack effector function. Notably, while TCRab + CD8ab + IELs in adult GF mice can persist for prolonged periods, they lose their effector function when fed an AF diet. IL-12 presumably produced by intestinal dendritic cells plays a critical role in the maintenance of TCRab + CD8ab + IELs and their effector functions. Importantly, mice lacking functional dietary antigen-induced TCRab + CD8ab + IELs exhibit a defect in early protection against a foodborne pathogen, Listeria monocytogenes. Collectively, these findings support that dietary antigen exposure drives the generation of innate-like cytotoxic IELs thatprovide rapid and local protection against foodborne-pathogens.