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

Erin E. West; Nicolas S. Merle; Marcin M. Kamiński; Gustavo Palacios; Dhaneshwar Kumar; Luopin Wang; Jack A. Bibby; Kirsten Overdahl; Alan K. Jarmusch; Simon Freeley; Duck Yeon Lee; J. Will Thompson; Zu Xi Yu; Naomi Taylor; Marc Sitbon; Douglas R. Green; Andrea Bohrer; Katrin D. Mayer-Barber; Behdad Afzali; Majid Kazemian; Sabine Scholl-Buergi; Daniela Karall; Martina Huemer; Claudia Kemper

doi:10.1016/j.immuni.2023.07.014

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

Erin E. West^*, Nicolas S. Merle, Marcin M. Kamiński, Gustavo Palacios, Dhaneshwar Kumar, Luopin Wang, Jack A. Bibby, Kirsten Overdahl, Alan K. Jarmusch, Simon Freeley, Duck Yeon Lee, J. Will Thompson, Zu Xi Yu, Naomi Taylor, Marc Sitbon, Douglas R. Green, Andrea Bohrer, Katrin D. Mayer-Barber, Behdad Afzali, Majid KazemianSabine Scholl-Buergi, Daniela Karall, Martina Huemer, Claudia Kemper^*

^*Corresponding author for this work

Institute of Systemic Inflamation Research

38 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Immunity
Volume	56
Issue number	9
Pages (from-to)	2036-2053.e12
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2023.07.014
Publication status	Published - 12.09.2023

Funding

We thank the patients and the healthy donors for their support, and Lisa St. John-Williams for technical assistance (metabolomics). The MHC class II tetramer to Influenza PR8 (NP311-325) was kindly provided by the NIH Tetramer Core. This work was financed by the National Heart, Lung, and Blood Institute of the NIH (grant 5K22HL125593 to M.K.), the Intramural Research Program of the NIH with support from the National Institute of Diabetes and Digestive and Kidney Diseases (project number ZIA/DK075149 to B.A.), the National Heart, Lung, and Blood Institute (project number ZIA/HL006223 to C.K.), and the Metabolomic Core of the National Institute of Environmental Health Sciences (project title “metabolic profiling of Th1 contraction” to E.E.W. Natalia Kunz, and C.K.). Supervision, E.E.W. B.A. M.K. and C.K.; conceptualization, E.E.W. and C.K.; methodology, E.E.W. M.M.K. K.O. A.K.J. D.-Y.L. N.T. M.S. D.R.G. M.K. B.A. and C.K.; project administration, C.K.; investigation, E.E.W. N.S.M. M.M.K. G.P. D. Kumar, L.W. J.A.B. K.O. S.F. D.-Y.L. J.W.T. Z.-X.Y. K.D.M.-B. S.S.-B. D. Karall, and M.H.; formal analysis, E.E.W. N.S.M. M.M.K. D. Kumar, L.W. J.A.B. K.O. A.K.J. D.-Y.L. J.W.T. Z.-X.Y. N.T. M.S. K.D.M.-B. B.A. M.K. S.S.-B. D. Karall, M.H. and C.K.; resources, M.S. K.D.M.-B. A.B. S.S.-B. D. Karall, and M.H.; visualization, E.E.W. B.A. M.K. and C.K.; writing – original draft, E.E.W. and C.K.; funding acquisition, E.E.W. and C.K. 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. We support inclusive, diverse, and equitable conduct of research. We thank the patients and the healthy donors for their support, and Lisa St. John-Williams for technical assistance (metabolomics). The MHC class II tetramer to Influenza PR8 (NP311-325) was kindly provided by the NIH Tetramer Core. This work was financed by the National Heart, Lung, and Blood Institute of the NIH (grant 5K22HL125593 to M.K.), the Intramural Research Program of the NIH with support from the National Institute of Diabetes and Digestive and Kidney Diseases (project number ZIA/DK075149 to B.A.), the National Heart, Lung, and Blood Institute (project number ZIA/HL006223 to C.K.), and the Metabolomic Core of the National Institute of Environmental Health Sciences (project title “metabolic profiling of Th1 contraction” to E.E.W., Natalia Kunz, and C.K.).

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.21-05 Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2023.07.014

Cite this

West, E. E., Merle, N. S., Kamiński, M. M., Palacios, G., Kumar, D., Wang, L., Bibby, J. A., Overdahl, K., Jarmusch, A. K., Freeley, S., Lee, D. Y., Thompson, J. W., Yu, Z. X., Taylor, N., Sitbon, M., Green, D. R., Bohrer, A., Mayer-Barber, K. D., Afzali, B., ... Kemper, C. (2023). Loss of CD4⁺ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection. Immunity, 56(9), 2036-2053.e12. https://doi.org/10.1016/j.immuni.2023.07.014

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

abstract = "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.",

author = "West, \{Erin E.\} and Merle, \{Nicolas S.\} and Kami{\'n}ski, \{Marcin M.\} and Gustavo Palacios and Dhaneshwar Kumar and Luopin Wang and Bibby, \{Jack A.\} and Kirsten Overdahl and Jarmusch, \{Alan K.\} and Simon Freeley and Lee, \{Duck Yeon\} and Thompson, \{J. Will\} and Yu, \{Zu Xi\} and Naomi Taylor and Marc Sitbon and Green, \{Douglas R.\} and Andrea Bohrer and Mayer-Barber, \{Katrin D.\} and Behdad Afzali and Majid Kazemian and Sabine Scholl-Buergi and Daniela Karall and Martina Huemer and Claudia Kemper",

note = "Publisher Copyright: {\textcopyright} 2023",

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month = sep,

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doi = "10.1016/j.immuni.2023.07.014",

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West, EE, Merle, NS, Kamiński, MM, Palacios, G, Kumar, D, Wang, L, Bibby, JA, Overdahl, K, Jarmusch, AK, Freeley, S, Lee, DY, Thompson, JW, Yu, ZX, Taylor, N, Sitbon, M, Green, DR, Bohrer, A, Mayer-Barber, KD, Afzali, B, Kazemian, M, Scholl-Buergi, S, Karall, D, Huemer, M & Kemper, C 2023, 'Loss of CD4⁺ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection', Immunity, vol. 56, no. 9, pp. 2036-2053.e12. https://doi.org/10.1016/j.immuni.2023.07.014

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T1 - Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection

AU - West, Erin E.

AU - Merle, Nicolas S.

AU - Kamiński, Marcin M.

AU - Palacios, Gustavo

AU - Kumar, Dhaneshwar

AU - Wang, Luopin

AU - Bibby, Jack A.

AU - Overdahl, Kirsten

AU - Jarmusch, Alan K.

AU - Freeley, Simon

AU - Lee, Duck Yeon

AU - Thompson, J. Will

AU - Yu, Zu Xi

AU - Taylor, Naomi

AU - Sitbon, Marc

AU - Green, Douglas R.

AU - Bohrer, Andrea

AU - Mayer-Barber, Katrin D.

AU - Afzali, Behdad

AU - Kazemian, Majid

AU - Scholl-Buergi, Sabine

AU - Karall, Daniela

AU - Huemer, Martina

AU - Kemper, Claudia

PY - 2023/9/12

Y1 - 2023/9/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85169831807

U2 - 10.1016/j.immuni.2023.07.014

DO - 10.1016/j.immuni.2023.07.014

M3 - Journal articles

C2 - 37572656

AN - SCOPUS:85169831807

SN - 1074-7613

VL - 56

SP - 2036-2053.e12

JO - Immunity

JF - Immunity

IS - 9

ER -