Supersulfide controls intestinal inflammation by suppressing CD4⁺ T cell proliferation

Area of Science:

• Immunology
• Metabolism
• Gastroenterology

Background:

• Inflammatory bowel disease (IBD) involves chronic intestinal inflammation with CD4+ T lymphocytes playing a key role.
• CD4+ T cell immune responses are regulated by metabolic pathways like oxidative phosphorylation and glycolysis.

Purpose of the Study:

• To investigate the role of CARS2/CPERS-dependent supersulfide metabolism in regulating CD4+ T cell proliferation and its implication in IBD.

Main Methods:

• Analysis of Cars2+/- mice for CD4+ T cell accumulation and colitis development.
• Assessing CD4+ T cell cycle entry and Trp53 expression.
• Treatment with glutathione trisulfide (GSSSG) in mouse models.
• Re-analysis of human CD4+ T cell gene datasets from IBD patients.
• In vitro proliferation assays of human CD4+ T cells with GSSSG.

Main Results:

• Cars2+/- mice showed increased effector/memory CD4+ T cells in the colon with age.
• Cars2+/- CD4+ T cells exhibited enhanced cell cycle entry and exacerbated colitis, which was ameliorated by GSSSG.
• Downregulation of CARS2 correlated with IBD pathogenesis in human datasets.
• GSSSG inhibited proliferation of human CD4+ T cells in vitro.

Conclusions:

• CARS2/CPERS-dependent supersulfide metabolism is crucial for maintaining intestinal effector/memory CD4+ T cell homeostasis.
• Disrupted supersulfide metabolism contributes to the development of gut inflammation in both mice and humans, suggesting therapeutic potential for GSSSG.