CD4 T cell intrinsic arginase 1 controls the kinetics of Th1 induction and contraction

Abstract Arginase 1 (ARG1), the enzyme catalyzing conversion of arginine to ornithine and urea, is a hallmark IL-10 producing immunosuppressive M2 macrophages, however ARG1 activity in T cells disputed. Here we demonstrate that Arg1, but not Arg2, expression induction key feature lung CD4 during mouse vivo influenza infection. Ablation cell-intrinsic Arg1 unexpectedly accelerated both virus-specific Th1 effector response its IL-10-associated contraction. Biologically, this led efficient viral clearance, yet significantly reduced pathology. Surprisingly, loss did result disturbed intracellular or polyamine levels. Instead, by employing unbiased transcriptomic metabolomic approaches, found deficiency triggered altered glutamine metabolism, rebalancing flux normalized deficient cell response. Further, role was distinct from its’ isoenzyme as ablation intrinsic Arg2 resulted normal responses, instead Th2 Th17 responses. Finally, rare patients with ARG1, healthy donors CRISPR-Cas9-mediated deletion, recapitulated data, demonstrating also plays human Collectively, functions an unexpected pace-keeper helper (Th1) responses implications for Th1-associated tissue pathologies. Supported grants NIH (5K22HL125593 M.K.) Intramural Research Program (NIDDK ZIA/DK075149 B.A. NHLBI ZIA/HL006223 C.K.)