AUTHOR=Tayama Shunichi , Kitamura Yuya , Hiraide Kyoga , Suzuki Hibiki , Li Jing , Yang Ziying , Mitsuwaka Ryoji , Kawajiri Akihisa , Sato Kosuke , Gao Feng , Nakai Taku , Okuyama Yuko , Numakura Tadahisa , Yamada Mitsuhiro , Ida Tomoaki , Morita Masanobu , Kawabe Takeshi , Akaike Takaaki , Ishii Naoto 

TITLE=Supersulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1506580

DOI=10.3389/fimmu.2025.1506580

ISSN=1664-3224

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. 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.