tetano
Editor, Senior Moderator
Immunity
. 2023 Aug 3;S1074-7613(23)00327-8.
doi: 10.1016/j.immuni.2023.07.014. Online ahead of print. Loss of CD4[SUP]+[/SUP] T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection
Erin E West[SUP] 1 [/SUP], Nicolas S Merle[SUP] 2 [/SUP], Marcin M Kamiński[SUP] 3 [/SUP], Gustavo Palacios[SUP] 3 [/SUP], Dhaneshwar Kumar[SUP] 4 [/SUP], Luopin Wang[SUP] 5 [/SUP], Jack A Bibby[SUP] 2 [/SUP], Kirsten Overdahl[SUP] 6 [/SUP], Alan K Jarmusch[SUP] 6 [/SUP], Simon Freeley[SUP] 7 [/SUP], Duck-Yeon Lee[SUP] 8 [/SUP], J Will Thompson[SUP] 9 [/SUP], Zu-Xi Yu[SUP] 10 [/SUP], Naomi Taylor[SUP] 11 [/SUP], Marc Sitbon[SUP] 11 [/SUP], Douglas R Green[SUP] 3 [/SUP], Andrea Bohrer[SUP] 12 [/SUP], Katrin D Mayer-Barber[SUP] 12 [/SUP], Behdad Afzali[SUP] 4 [/SUP], Majid Kazemian[SUP] 5 [/SUP], Sabine Scholl-Buergi[SUP] 13 [/SUP], Daniela Karall[SUP] 13 [/SUP], Martina Huemer[SUP] 14 [/SUP], Claudia Kemper[SUP] 15 [/SUP]
Affiliations
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[SUP]+[/SUP] T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4[SUP]+[/SUP] 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[SUP]+[/SUP] T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4[SUP]+[/SUP] T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.
Keywords: IFN-γ; IL-10; Th1 immunity; arginase 1; arginase 1 deficiency; autoimmunity; cell metabolism; complement; glutamine; influenza infection.
. 2023 Aug 3;S1074-7613(23)00327-8.
doi: 10.1016/j.immuni.2023.07.014. Online ahead of print. Loss of CD4[SUP]+[/SUP] T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection
Erin E West[SUP] 1 [/SUP], Nicolas S Merle[SUP] 2 [/SUP], Marcin M Kamiński[SUP] 3 [/SUP], Gustavo Palacios[SUP] 3 [/SUP], Dhaneshwar Kumar[SUP] 4 [/SUP], Luopin Wang[SUP] 5 [/SUP], Jack A Bibby[SUP] 2 [/SUP], Kirsten Overdahl[SUP] 6 [/SUP], Alan K Jarmusch[SUP] 6 [/SUP], Simon Freeley[SUP] 7 [/SUP], Duck-Yeon Lee[SUP] 8 [/SUP], J Will Thompson[SUP] 9 [/SUP], Zu-Xi Yu[SUP] 10 [/SUP], Naomi Taylor[SUP] 11 [/SUP], Marc Sitbon[SUP] 11 [/SUP], Douglas R Green[SUP] 3 [/SUP], Andrea Bohrer[SUP] 12 [/SUP], Katrin D Mayer-Barber[SUP] 12 [/SUP], Behdad Afzali[SUP] 4 [/SUP], Majid Kazemian[SUP] 5 [/SUP], Sabine Scholl-Buergi[SUP] 13 [/SUP], Daniela Karall[SUP] 13 [/SUP], Martina Huemer[SUP] 14 [/SUP], Claudia Kemper[SUP] 15 [/SUP]
Affiliations
- PMID: 37572656
- DOI: 10.1016/j.immuni.2023.07.014
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[SUP]+[/SUP] T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4[SUP]+[/SUP] 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[SUP]+[/SUP] T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4[SUP]+[/SUP] T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.
Keywords: IFN-γ; IL-10; Th1 immunity; arginase 1; arginase 1 deficiency; autoimmunity; cell metabolism; complement; glutamine; influenza infection.