Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation

Abstract

SUMMARYAmino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4+T cell subset requirements for specific AA remains uncertain. Here we tested CD4+T cell AA demands within vitroand multiplein vivoCRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over timein vitroandin vivolung inflammation, SLC38A1 was critical for Th1 but not Th17 cell-driven Experimental Autoimmune Encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation. Similarly, pharmacological inhibition of SLC38 transporters delayed EAE but did not affect lung inflammation. Subset- and tissue-specific dependencies of CD4+T cells on AA transporters may guide selective immunotherapies.HIGHLIGHTST cells dynamically regulate glutamine amino acid transporters when activatedSLC38A1 supports Th1 cell mTORC1 and proliferation by redox and hexosamine pathwaysTargeting SLC38A1 does not affect lung inflammation but delays IBD and EAENutrient transporter needs of T cell subsets vary based on disease and tissue site