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. DruckerMatthias Nahrendorf, Filip K. Swirski

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)115-119
Number of pages5
JournalNature
Volume566
Issue number7742
DOIs
Publication statusPublished - 2019 Feb 7
Externally publishedYes

ASJC Scopus subject areas

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    He, S., Kahles, F., Rattik, S., Nairz, M., McAlpine, C. S., Anzai, A., Selgrade, D., Fenn, A. M., Chan, C. T., Mindur, J. E., Valet, C., Poller, W. C., Halle, L., Rotllan, N., Iwamoto, Y., Wojtkiewicz, G. R., Weissleder, R., Libby, P., Fernández-Hernando, C., ... Swirski, F. K. (2019). Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease. Nature, 566(7742), 115-119. https://doi.org/10.1038/s41586-018-0849-9