Obesity reduces mTORC1 activity in mucosal-associated invariant T cells, driving defective metabolic and functional responses
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- University College Dublin
- Trinity College Dublin
- Department of Biology, Institute of Immunology, Maynooth University, Maynooth, County Kildare W23 F2K8, Ireland.
- National Children's Research Centre, Dublin 12, Ireland.
- Dana-Farber Cancer Institute
- University of Dundee
- Queen's University, Belfast
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.
|Number of pages||8|
|Journal||Journal of Immunology|
|Early online date||10 May 2019|
|Publication status||Published - 15 Jun 2019|