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

Autor:	Sugiura A; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Beier KL; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Chi C; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Heintzman DR; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Ye X; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Wolf MM; Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Patterson AR; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Cephus JY; Department of Medicine, Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Hong HS; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109 USA.; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 USA., Lyssiotis CA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109 USA.; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 USA.; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109 USA., Newcomb DC; Department of Medicine, Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN 37232, USA.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Rathmell JC; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 13. Date of Electronic Publication: 2023 Sep 13.
DOI:	10.1101/2023.09.13.557496
Abstrakt:	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. Competing Interests: DECLARATION OF INTERESTS J.C.R. is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics, a scientific advisory board member and stockholder of Caribou Biosciences, a member of the scientific advisory board of Nirogy Therapeutics, has consulted for Merck, Pfizer, and Mitobridge within the past three years, and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. In the past three years, C.A.L. has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015).
Databáze:	MEDLINE
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