Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation
Year: 2023
Type: preprint
Abstract: SUMMARY 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 AA remains uncertain. Here we tested CD4 + T cell AA demands with in vitro and multiple in vivo CRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over time in vitro and in vivo 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 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. HIGHLIGHTS T cells dynamically regulate glutamine amino acid transporters when activated SLC38A1 supports Th1 cell mTORC1 and proliferation by redox and hexosamine pathways Targeting SLC38A1 does not affect lung inflammation but delays IBD and EAE Nutrient transporter needs of T cell subsets vary based on disease and tissue site
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
Funders: Vanderbilt University, Vanderbilt-Ingram Cancer Center, Lupus Research Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1002678292, G1280513408, G1388609297, G2006259475, Androgens inhibit IL-33 production and airway inflammation, Leica Bond RX, G275963511, G2939754950, G3152736877, G3269002440, G3272792225, G3726302789, Medical Scientist Training Program, G4513176822, G5853943267, G7220527126, G725763919, Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis, Targeting T cell glutamine metabolism in severe asthma, G8953775245, G9000060478, G9000064184, G9000081609, G9000089795, G9000127534, G9000130502, Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease, Metabolic barriers to T cell activation in clear cell renal cell carcinoma
OpenAlex ID: W4386744840