Free Fatty Acids Induce Impairment of Mitochondrial Function and Cytokine Expression in Mucosal-Associated Invariant T (MAIT) Cells in NAFLD

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide. Recent data suggest alterations of the immune landscape in NAFLD, rendering the liver microenvironment permissive for the development of hepatocellular carcinoma. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells in patients with NAFLD and aimed to decipher the effect of the metabolism on MAIT cell function in NAFLD. MAIT cells were isolated from peripheral blood of NAFLD patients or controls and stimulated in vitro in complete or fatty acid rich medium. MAIT cell phenotype and function were analysed by multi-colour flow cytometry. MAIT cell metabolism was investigated by metabolic flux analysis. We show that MAIT cell frequency is significantly decreased in peripheral blood of patients with NAFLD. Compared to controls, NAFLD MAIT cells expressed significantly higher levels of activation markers and effector cytokines ex vivo, suggesting MAIT cell activation in NAFLD. However, upon in vitro stimulation with IL-12 and IL18, MAIT cells from NAFLD patients failed to upregulate expression of effector cytokines, i. e. IFNg, Granzyme B and IL-17A. MAIT cell effector function was dependent on glycolysis and oxidative phosphorylation in NAFLD patients. When cultured with free fatty acids, MAIT cells preferentially took up oleic and linoleic acid, which induced a significant decline in IFNg expression by MAIT cells. Interestingly, oleic and linoleic acid disrupted mitochondrial potential in MAIT cells and induced cell death, while mitochondrial mass remained unaffected. Our results show that MAIT cells are highly activated but dysfunctional in NAFLD.