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


    O'Brien, Aisling and Loftus, Roisin M. and Pisarska, Marta M. and Tobin, Laura M. and Bergin, Ronan and Wood, Nicole A.W. and Foley, Cathriona and Mat, Arimin and Tinley, Frances C. and Bannan, Ciaran and Sommerville, Gary and Veerapen, Natacha and Besra, Gurdyal S. and Sinclair, Linda V. and Moynagh, Paul N. and Lynch, Lydia and Finlay, David K. and O'Shea, Donal and Hogan, Andrew (2019) Obesity Reduces mTORC1 Activity in Mucosal-Associated Invariant T Cells, Driving Defective Metabolic and Functional Responses. Journal of Immunology, 202. pp. 3404-3411. ISSN 0022-1767

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    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-g 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-g 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.

    Item Type: Article
    Additional Information: This work was supported by the National Children’s Research Centre. A.E.H. and D.O. are funded by the Health Research Board (HRB) (Grant RA-POR-2014-593), and A.O. is funded by the HRB Centre for Health and Diet Research (Grant HRC2014/13), both of which are funded by the Irish HRB. M.M.P., N.A.W.W., and A.E.H. are supported by the National Children’s Research Centre. The Seahorse XF-96 Analyzer is funded by Science Foundation Ireland Grant 16/RI/3399. Cite as:
    Keywords: Obesity; Reduces; mTORC1 Activity; Mucosal-Associated Invariant T Cells; Defective Metabolic; Functional; Responses;
    Academic Unit: Faculty of Science and Engineering > Biology
    Faculty of Science and Engineering > Research Institutes > Human Health Institute
    Item ID: 13450
    Identification Number: https://doi.org/10.4049/jimmunol.1801600
    Depositing User: Professor Paul Moynagh
    Date Deposited: 23 Oct 2020 13:45
    Journal or Publication Title: Journal of Immunology
    Publisher: American Association of Immunologists
    Refereed: Yes
    Funders: National Children’s Research Centre, Health Research Board (HRB), Science Foundation Ireland (SFI)
    URI:

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