Divergent metabolic programs control two populations of MAIT cells that protect the lung

Although mucosal associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127-Klrg1+ and CD127+Klrg1- antigen-adapted populations that differed for their transcriptome, function and localization in lung tissue. These populations remained altered from steady-state for months as stable, separate MAIT cell lineages with enhanced effector programs and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic program, which was critical for their maintenance and IL-17A synthesis. This program was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant, but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis. They responded vigorously to cytokines and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccinations and immunotherapies. Overall design: RNAseq of mouse MAIT cells sorted by Tetramer, TCR and dump exclusion