Supersulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation

作者：Shunichi Tayama, Yuya Kitamura, Kyoga Hiraide, Hibiki Suzuki, Jing Li, Ziying Yang, Ryoji Mitsuwaka, Akihisa Kawajiri, Kosuke Sato, Feng Gao, Taku Nakai, Yuko Okuyama, Tadahisa Numakura, Mitsuhiro Yamada, Tomoaki Ida, Masanobu Morita, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1506580 · 被引用次数：3 · 研究领域：Immune cells in cancer、Immune Cell Function and Interaction、IL-33, ST2, and ILC Pathways

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, Cars2 +/- mice exhibited 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 with reduced expression of a cell cycle inhibitor Trp53 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 CARS2 was associated with pathogenesis of IBD, and indeed, addition of GSSSG inhibited human CD4 + T cell proliferation in vitro . 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.