GSE126169
MAIT cell RNA sequencing
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-gamma production, which is a critical effector function of MAIT cells in host defence. Hence there is increased urgency to characterise 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 signalling and SLC7A5 amino acid transport. Collectively our data details the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlights mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses. We report on MAIT cells isolated from lean and obese adults Overall design: MAIT cells from 5 healthy bodyweight donors and 4 morbidly obese donors