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 Bibby, Kirsten E. Overdahl, Alan K. Jarmusch, Simon Freeley, Duck‐Yeon Lee, J. Will Thompson, Zu‐Xi Yu, Naomi Taylor, Marc Sitbon, Douglas R. Green, Andrea C. Bohrer, Katrin D. Mayer-Barber, Behdad Afzali, Majid Kazemian, Sabine Scholl‐Buergi, Daniela Karall, Martina Huemer, Claudia Kemper
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.