Loss of CD4 + T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.

Autor:	West EE; Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address: erin.west@nih.gov., Merle NS; Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA., Kamiński MM; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Palacios G; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Kumar D; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA., Wang L; Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA., Bibby JA; Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA., Overdahl K; Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC, USA., Jarmusch AK; Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC, USA., Freeley S; School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Lee DY; Biochemistry Core, NHLBI, NIH, Bethesda, MD, USA., Thompson JW; Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA., Yu ZX; Pathology Core, NHLBI, NIH, Bethesda, MD, USA., Taylor N; Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, MD, USA; Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France., Sitbon M; Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, MD, USA; Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France., Green DR; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Bohrer A; Inflammation and Innate Immunity Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA., Mayer-Barber KD; Inflammation and Innate Immunity Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA., Afzali B; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA., Kazemian M; Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA., Scholl-Buergi S; Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria., Karall D; Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria., Huemer M; Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Pediatric Endocrinology and Diabetology, University Children's Hospital Basel, Basel, Switzerland; Department of Pediatrics, Landeskrankenhaus (LKH) Bregenz, Bregenz, Austria., Kemper C; Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address: claudia.kemper@nih.gov.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2023 Sep 12; Vol. 56 (9), pp. 2036-2053.e12. Date of Electronic Publication: 2023 Aug 11.
DOI:	10.1016/j.immuni.2023.07.014
Abstrakt:	Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4 + T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4 + T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4 + T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4 + T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies. Competing Interests: Declaration of interests M.S. is an inventor on a patent describing the use of RBD ligands for cell-surface evaluation of CAT1/solute carrier family 7 member 1 (SLC7A1) and other solute carrier (SLC) expression (N.T. gave up her rights); he is a co-founder and head of the scientific board of METAFORA-Biosystems, a start-up company that focuses on metabolite transporters under physiological and pathological conditions. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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