Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease

Shun He (), Florian Kahles, Sara Rattik, Manfred Nairz, Cameron S. McAlpine, Atsushi Anzai, Daniel Selgrade, Ashley M. Fenn, Christopher T. Chan, John E. Mindur, Colin Valet, Wolfram C. Poller, Lennard Halle, Noemi Rotllan, Yoshiko Iwamoto, Gregory R. Wojtkiewicz, Ralph Weissleder, Peter Libby, Carlos Fernández-Hernando, Daniel J. Drucker, Matthias Nahrendorf and Filip K. Swirski ()
Additional contact information
Shun He: Massachusetts General Hospital and Harvard Medical School
Florian Kahles: Massachusetts General Hospital and Harvard Medical School
Sara Rattik: Massachusetts General Hospital and Harvard Medical School
Manfred Nairz: Massachusetts General Hospital and Harvard Medical School
Cameron S. McAlpine: Massachusetts General Hospital and Harvard Medical School
Atsushi Anzai: Massachusetts General Hospital and Harvard Medical School
Daniel Selgrade: Massachusetts General Hospital and Harvard Medical School
Ashley M. Fenn: Massachusetts General Hospital and Harvard Medical School
Christopher T. Chan: Massachusetts General Hospital and Harvard Medical School
John E. Mindur: Massachusetts General Hospital and Harvard Medical School
Colin Valet: Massachusetts General Hospital and Harvard Medical School
Wolfram C. Poller: Massachusetts General Hospital and Harvard Medical School
Lennard Halle: Massachusetts General Hospital and Harvard Medical School
Noemi Rotllan: Yale University School of Medicine
Yoshiko Iwamoto: Massachusetts General Hospital and Harvard Medical School
Gregory R. Wojtkiewicz: Massachusetts General Hospital and Harvard Medical School
Ralph Weissleder: Massachusetts General Hospital and Harvard Medical School
Peter Libby: Brigham and Women’s Hospital
Carlos Fernández-Hernando: Yale University School of Medicine
Daniel J. Drucker: Mount Sinai Hospital, University of Toronto
Matthias Nahrendorf: Massachusetts General Hospital and Harvard Medical School
Filip K. Swirski: Massachusetts General Hospital and Harvard Medical School

Nature, 2019, vol. 566, issue 7742, 115-119

Abstract: Abstract The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways1, 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-12, 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.

Date: 2019
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DOI: 10.1038/s41586-018-0849-9

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