TY - JOUR
T1 - Obesity reduces mTORC1 activity in mucosal-associated invariant T cells, driving defective metabolic and functional responses
AU - O'Brien, Aisling
AU - Loftus, Roisin M
AU - Pisarska, Marta M
AU - Tobin, Laura M
AU - Bergin, Ronan
AU - Wood, Nicole A W
AU - Foley, Cathriona
AU - Mat, Arimin
AU - Tinley, Frances C
AU - Bannan, Ciaran
AU - Sommerville, Gary
AU - Veerapen, Natacha
AU - Besra, Gurdyal S
AU - Sinclair, Linda V
AU - Moynagh, Paul N
AU - Lynch, Lydia
AU - Finlay, David K
AU - O'Shea, Donal
AU - Hogan, Andrew E
N1 - Copyright © 2019 by The American Association of Immunologists, Inc.
PY - 2019/6/15
Y1 - 2019/6/15
N2 - Obesity underpins the development of numerous chronic diseases, such as type II diabetes mellitus. It is well established that obesity negatively alters immune cell frequencies and functions. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells, which we have previously reported are dysregulated in obesity, with altered circulating and adipose tissue frequencies and a reduction in their IFN-γ production, which is a critical effector function of MAIT cells in host defense. Hence, there is increased urgency to characterize the key molecular mechanisms that drive MAIT cell effector functions and to identify those which are impaired in the obesity setting. In this study, we found that MAIT cells significantly upregulate their rates of glycolysis upon activation in an mTORC1-dependent manner, and this is essential for MAIT cell IFN-γ production. Furthermore, we show that mTORC1 activation is dependent on amino acid transport via SLC7A5. In obese patients, using RNA sequencing, Seahorse analysis, and a series of in vitro experiments, we demonstrate that MAIT cells isolated from obese adults display defective glycolytic metabolism, mTORC1 signaling, and SLC7A5 aa transport. Collectively, our data detail the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlight mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses.
AB - Obesity underpins the development of numerous chronic diseases, such as type II diabetes mellitus. It is well established that obesity negatively alters immune cell frequencies and functions. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells, which we have previously reported are dysregulated in obesity, with altered circulating and adipose tissue frequencies and a reduction in their IFN-γ production, which is a critical effector function of MAIT cells in host defense. Hence, there is increased urgency to characterize the key molecular mechanisms that drive MAIT cell effector functions and to identify those which are impaired in the obesity setting. In this study, we found that MAIT cells significantly upregulate their rates of glycolysis upon activation in an mTORC1-dependent manner, and this is essential for MAIT cell IFN-γ production. Furthermore, we show that mTORC1 activation is dependent on amino acid transport via SLC7A5. In obese patients, using RNA sequencing, Seahorse analysis, and a series of in vitro experiments, we demonstrate that MAIT cells isolated from obese adults display defective glycolytic metabolism, mTORC1 signaling, and SLC7A5 aa transport. Collectively, our data detail the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlight mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses.
UR - http://www.scopus.com/inward/record.url?scp=85067215223&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1801600
DO - 10.4049/jimmunol.1801600
M3 - Article
C2 - 31076528
SN - 0022-1767
VL - 202
SP - 3404
EP - 3411
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -