Reactive persulfide controls intestinal inflammation by suppressing CD4⁺ T cell proliferation

Abstract Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation where CD4 +T lymphocytes play an essential role. Accumulating evidence suggests that immune responses driven by CD4 +T cells are critically regulated by various metabolic pathways including oxidative phosphorylation and glycolysis. In addition, we have recently identified a novel, sulfur metabolic pathway that is controlled by mitochondrial cysteinyl-tRNA synthetase (CARS2/CPERS) through the production of a highly reactive sulfur metabolite cysteine persulfide (CysSSH). However, the functional significance of this metabolic signaling in CD4 +T lymphocytes remains unclear. Here we show using Cars2 +/−animals that CARS2/CPERS-dependent persulfide metabolism restrains CD4 +T cell proliferation in a cell-intrinsic manner. Under steady state, Cars2 +/−mice exhibited a spontaneous accumulation of effector/memory CD4 +T cells in the colon with age. In lymphopenic conditions, Cars2 +/−CD4 +T cells showed enhanced cell cycle entry and an exacerbated form of colitis, the latter response being rescued by treatment with an endogenous persulfide donor. Furthermore, re-analysis of publicly available gene datasets of human CD4 +T lymphocytes revealed that downregulation of CARS2 was associated with pathogenesis of IBD, and indeed addition of persulfide donor inhibited CD4 +T cell proliferation in vitro. Together these observations reveal that CARS2/CPERS-dependent persulfide metabolism is essential for homeostasis of intestinal effector/memory CD4 +T cells, and further suggest that dysregulation of the same metabolic pathway can lead to development of gut inflammation in both mice and humans. Supported by grants from Japanese Society for the Promotion of Science KAKENHI grant numbers JP20J20344