Supersulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation

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. Here we show that CARS2/CPERS-dependent supersulfide metabolism restrains CD4⁺ T cell proliferation in a cell-intrinsic manner. Under steady state, <i>Cars2</i> ^+/- mice exhibited spontaneous accumulation of effector/memory CD4⁺ T cells in the colon with age. In lymphopenic conditions, <i>Cars2</i> ^+/- CD4⁺ T cells showed enhanced cell cycle entry with reduced expression of a cell cycle inhibitor <i>Trp53</i> and triggered an exacerbated form of colitis, the response being rescued by treatment with a supersulfide donor glutathione trisulfide (GSSSG). Furthermore, re-analysis of publicly available gene datasets of human colonic CD4⁺ T lymphocytes revealed that downregulation of <i>CARS2</i> was associated with pathogenesis of IBD, and indeed, addition of GSSSG inhibited human CD4⁺ T cell proliferation <i>in vitro</i>. Together these observations reveal that CARS2/CPERS-dependent supersulfide 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 both in mice and humans.