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

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