Metabolic fuel choices control MAIT cell functions at homeostasis and after infection

Abstract Mucosal-associated-invariant-T (MAIT) cells are an innate-like T cell subset that recognizes microbial-derived vitamin B metabolites. In contrast to conventional T cells, MAIT cells have an antigen-experienced phenotype and express memory markers by default. When activated, MAIT cells rapidly produce copious amounts of cytokines, resembling IFNg+ Th1- or IL-17+ Th17 effectors cells. While memory-like vs effector-like states in conventional CD4 and CD8 T cells are controlled by mutually exclusive metabolic states, the question remains as to which metabolic programs MAIT cells adopt at steady-state and after infection. Here we integrate scRNA-seq analysis with single-cell metabolic characterization of MAIT cells from humans and mice. We discovered a memory-like metabolic program that is acquired in the thymus and at steady state in the periphery. We identify a novel cluster of circulatory MAIT cells which is metabolically similar to IFNg+ MAIT1-like cells and preferentially consumes glucose. MAIT17 clusters, most prevalent in mice, uniquely engage in fatty acid uptake and mitochondrial metabolism. Following exposure to bacteria, mouse MAIT cells expand as CD127−KLRG1+ and CD127+KLRG1− populations that adopt divergent transcriptomic and metabolic profiles with enhanced functionality. They remain altered long-term. CD127+, but not KLRG1+ MAIT cells engage in MAIT17-like metabolic and effector pathways and protect mice from lung infection with Streptococcus pneumoniae. In contrast, KLRG1+ MAIT cells depend on Hif1a-driven glycolysis and remain metabolically dormant but ready to respond, more rapidly engaging multiple metabolic programs to protect from viral infection. Supported by R01AI137230 (MK), R01AI71922 (MK), Wellcome Trust 210842_Z_18_Z (TR)