Metabolic fuel choices control mouse and human MAIT cell functions 2703

Abstract Description Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that recognize Vitamin B metabolites. Although MAIT cells provide rapid, innate-like responses, they are not pre-set and memory-like responses have been described. The importance of metabolism for controlling these responses, however, is unknown. Our data indicate that different MAIT functions require distinct metabolic programs. Following antigen exposure, mouse MAIT cells expanded as antigen-adapted populations marked by CD127 and Klrg1. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic program and active autophagy, which was critical for IL-17A synthesis. In contrast, Klrg1+ MAIT cells had dormant mitochondria and depended instead on Vhl-driven glycolysis for IFN-γ production. Although human MAIT cells do not fit easily into MAIT1 and MAIT17 categories, their metabolism differed from conventional T cells, specifically by engaging a fatty acid fueled program that is evident in lung and blood. Lipid metabolism was further induced following exposure to antigen in vitro. Based on scRNA-seq, metabolomic and functional characterization, these human antigen adapted (aa) MAIT cells engaged functional and metabolic programs that depended on the nature of the re-stimulation with cytokines, TCR signals or both. Elucidating how metabolic programs shape functional responses of aaMAIT cells will be crucial for optimizing the clinical application of MAIT cells for adoptive cell immunotherapy. Funding Sources Supported by SDDRC PF23/24-02 (TR), Tullie and Rickie SPARK Awards (TR), Kyowa Kirin US KKUS (TR + MK) Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)