Amino 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 AAs remains uncertain. Here, we tested CD4 + T cell AA demands with in vitro and in vivo CRISPR screens and identified subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion in vivo in lung 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 glutamine uptake and disrupting hexosamine biosynthesis and redox regulation. Pharmacological inhibition of SLC38 transporters also delayed Th1-mediated EAE but did not affect lung inflammation. CD4 + T cells thus have subset- and tissue-specific nutrient transporter dependencies that may guide new metabolic approaches for selective immunotherapies. • SLC38A1 contributes to glutamine uptake to aid Th1, but not Th17, cell proliferation • Th1 cell redox and hexosamine pathways selectively depend on SLC38A1 • SLC38A1 plays tissue-selective roles in gut and brain, but not lung, inflammation • T cell nutrient transporter needs vary based on subset, disease, and tissue site Metabolic demands and mechanisms of nutrient uptake shape T cell function and offer new therapeutic opportunities, but selective targeting remains challenging. Here, in vivo CRISPR screens show that CD4 T cell metabolism and nutrient uptake vary based on both cell subset and the tissue and inflammatory site.
Sugiura et al. (Sun,) studied this question.