Obesity Reduces mTORC1 Activity in Mucosal-Associated Invariant T Cells, Driving Defective Metabolic and Functional Responses

Aisling O'Brien, Roisin M. Loftus, Marta M. Pisarska, Laura M. Tobin, Ronan Bergin, Nicole A. W. Wood, Cathriona Foley, Arimin Mat, Frances C. Tinley, Ciaran Bannan, Gary Sommerville, Natacha Veerapen, Gurdyal S. Besra, Linda V. Sinclair, Paul N. Moynagh, Lydia Lynch, David K. Finlay, Donal O'Shea, Andrew E. Hogan (Lead / Corresponding author)

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3404-3411
Number of pages8
JournalJournal of Immunology
Volume202
Issue number12
Early online date10 May 2019
DOIs
Publication statusPublished - 15 Jun 2019

Fingerprint Dive into the research topics of 'Obesity Reduces mTORC1 Activity in Mucosal-Associated Invariant T Cells, Driving Defective Metabolic and Functional Responses'. Together they form a unique fingerprint.

Cite this