TY - JOUR
T1 - Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease
AU - He, Shun
AU - Kahles, Florian
AU - Rattik, Sara
AU - Nairz, Manfred
AU - McAlpine, Cameron S.
AU - Anzai, Atsushi
AU - Selgrade, Daniel
AU - Fenn, Ashley M.
AU - Chan, Christopher T.
AU - Mindur, John E.
AU - Valet, Colin
AU - Poller, Wolfram C.
AU - Halle, Lennard
AU - Rotllan, Noemi
AU - Iwamoto, Yoshiko
AU - Wojtkiewicz, Gregory R.
AU - Weissleder, Ralph
AU - Libby, Peter
AU - Fernández-Hernando, Carlos
AU - Drucker, Daniel J.
AU - Nahrendorf, Matthias
AU - Swirski, Filip K.
N1 - Funding Information:
Acknowledgements This work was supported by NIH grants R35 HL135752, R01 HL128264, P01 HL131478, the AHA EIA and the Patricia and Scott Eston MGH Research Scholar (to F.K.S.). S.H. was supported by an AHA Postdoctoral Award (16POST27250124); F.K. and W.C.P. by the German Research Foundation (DFG); S.R. was supported by a postdoctoral fellowship from the Swedish Research Council; M. Nairz was supported by a FWF Erwin Schroedinger Fellowship (J3486-B13); J.E.M. was supported by a NIH training grant (T32 AI118692); L.H. was supported by a Boehringer Ingelheim Fonds MD Fellowship; and D.J.D. was supported by a CIHR grant 154321, the Canada Research Chairs program and a BBDC-Novo Nordisk Chair in Incretin biology. We thank K. Joyes for copy-editing the manuscript.
Funding Information:
Competing interests The General Hospital Corporation has filed a US patent application 62/771,668 with the US Patent and Trademark office entitled ‘Targeting intraepithelial leukocytes for treatment of cardiometabolic diseases’, which names F.K.S. and S.H. as inventors. D.J.D. has served as an advisor or consultant to Intarcia, Forkhead Biopharmaceuticals Inc., Kallyope Inc., Merck Research Laboratories, Pfizer Inc., Novo Nordisk Inc. and Zafgen Inc. Mount Sinai receives funding from GSK, Merck and Novo Nordisk for GLP-1-related studies in the Drucker laboratory.
Publisher Copyright:
© 2019, Springer Nature Limited.
PY - 2019/2/7
Y1 - 2019/2/7
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85060997991&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0849-9
DO - 10.1038/s41586-018-0849-9
M3 - Article
C2 - 30700910
AN - SCOPUS:85060997991
VL - 566
SP - 115
EP - 119
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 7742
ER -