Characterisation of Mucosal Associated Invariant T cells function and metabolism in health and obesity

Obesity has developed into a worldwide pandemic, affecting individuals regardless of their socio-economic status, gender or age. It is associated with development of multiple co-morbidities including type 2 diabetes mellitus, which have been shown to be underpinned by inflammation. Indeed, excessive adiposity has been shown to be associated with a large dysregulation of immune cell function, including altered phenotype of mucosal-associated invariant T (MAIT) cells. MAIT cells from people with obesity were shown to have enhanced IL-17 production, accompanied by impaired IFNγ expression. As of now, very little is known about the control of MAIT cell function, therefore more research is required to understand their biology in order to identify the altered process, which leads to their dysfunction in obesity. Immunometabolism of MAIT cells became the focus of this thesis as previous data indicated it as a key biological process that controls immune cell function. Here we confirmed previously published data, showing that MAIT cells are potent producers of IFNγ and IL-17 cytokines and that MAIT cells can proliferate and expand upon stimulation. In addition, we reported that MAIT cells enhance glycolysis upon activation, which in turn is controlled by the influx of amino acids into the cells via LAT1 amino acid transporters. Glycolytic metabolism was required for successful IFNγ production as well as proliferation and expansion of MAIT cells. People with obesity have impaired IFNγ expression and MAIT cell expansion that was accompanied by impaired glycolytic metabolism. Collectively our data indicates that MAIT cells effector functions are in part controlled by the intrinsic metabolic pathways including the glycolytic metabolism. Defect in glycolysis or glycolysis-associated pathways as observed in obesity, leads to their dysfunction and altered immune cells responses