Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease

• Published in: Nature (London) Vol. 566; no. 7742; pp. 115 - 119
• Main Authors: He, Shun, Kahles, Florian, Rattik, Sara, Nairz, Manfred, McAlpine, Cameron S., Anzai, Atsushi, Selgrade, Daniel, Fenn, Ashley M., Chan, Christopher T., Mindur, John E., Valet, Colin, Poller, Wolfram C., Halle, Lennard, Rotllan, Noemi, Iwamoto, Yoshiko, Wojtkiewicz, Gregory R., Weissleder, Ralph, Libby, Peter, Fernández-Hernando, Carlos, Drucker, Daniel J., Nahrendorf, Matthias, Swirski, Filip K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13/21; 13/31; 14/1; 14/34; 45/77; 45/90; 59/78; 631/443/319; 631/443/592/75; 64/60; 82/1; 9/10; Animals; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Bioavailability; Bone marrow; Carbohydrate metabolism; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - genetics; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - prevention & control; Cholesterol; Control; Control systems; Development and progression; Diabetes; Diabetes mellitus; Diet; Digestive system; Disease Models, Animal; Disease Progression; Eating; Enterocytes - cytology; Enterocytes - metabolism; Fat metabolism; Fats; Female; Food intake; Gastrointestinal tract; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - metabolism; High fat diet; Humanities and Social Sciences; Hypertension; Immune system; Insulin; Integrin beta Chains - genetics; Integrin beta Chains - metabolism; Integrins; Intestine, Small - cytology; Intraepithelial Lymphocytes - metabolism; Letter; Lipoproteins; Lymphocytes; Lymphocytes T; Male; Metabolic syndrome; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Metabolic Syndrome - prevention & control; Metabolism; Mice; multidisciplinary; Nutrients; Nutritive value; Obesity; Peptides; Physiological aspects; Risk factors; Rodents; Science; Science (multidisciplinary); Small intestine; Sugar; T cells; Tomography; Triglycerides
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0849-9

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways 1 , how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells—integrin β7 + natural gut intraepithelial T lymphocytes (natural IELs)—that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin β7 − mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-1 2 , which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health. Integrin β7-dependent Glp1r high natural gut intraepithelial T lymphocytes that reside in the small intestine modulate dietary metabolism in mice by restricting the bioavailability of GLP-1.