Gut intraepithelial T cells calibrate dietary metabolism and contribute to the development of metabolic syndrome

Abstract

Tissue resident immune cells undergo phenotypic transformation to maintain the integrity and function of host tissues. Upon extravasation from circulation, lymphocytes in the gut acquire homeostatic mechanisms outside the adaptive and innate immune response. We hypothesize that integrin β7+ natural gut intraepithelial T lymphocytes (natural IELs) dispersed throughout the small intestine’s enterocyte layer suppress systemic metabolism. β7–/– mice deficient in natural IELs in the gut epithelial layer demonstrate lean body mass and hyperactive metabolism that protect from the development of metabolic syndrome when fed a diet high in fat and sugar. By examining cardiovascular disease resistance and metabolic function, we demonstrate a novel mechanism for endocrine regulation of whole body metabolism by natural IELs via receptor-mediated sequestration of enterocyte-derived incretin glucagon-like peptide-1 (GLP-1). This homeostatic function of natural IELs represents a rheostatic checkpoint by which IELs mediate the gut response to food intake and become dysregulated in response to nutrient overabundance.