St. Jude Children's Research Hospital scientists discovered that regulatory T cells co-opt the COMPASS gene-regulatory pathway and its key gene Wdr82 to maintain gut immune tolerance. Published in Science Advances, the study shows that deleting Wdr82 in T cells causes lethal inflammation in mouse models, which can be reversed by restoring functional regulatory T cells or using antibiotics. The findings demonstrate asymmetric gene functions across T-cell subtypes, potentially re-evaluating dismissed genetic variants in inflammatory bowel disease and autoimmune conditions.
Discovery of Wdr82 and COMPASS pathway
- ▪A study published in Science Advances found that regulatory T cells co-opt the COMPASS gene expression pathway to suppress immune responses against gut microbiota.
- ▪A study led by St. Jude researcher Wenjun Huang and published in Science Advances showed that Wdr82 is a key component of the gene activation pathway COMPASS.
- ▪St. Jude Children's Research Hospital scientists used a CRISPR screen to identify that the gene Wdr82 plays an essential role in maintaining intestinal immune tolerance.
- ▪The COMPASS gene-regulatory pathway enables regulatory T cells under normal conditions to prevent lethal inflammation and autoimmunity in the human intestine.
Effects of Wdr82 deletion in mouse models
- ▪Introducing functional regulatory T cells with intact Wdr82 to Wdr82-deleted mouse models reversed the disease process and prevented death.
- ▪Deleting the Wdr82 gene in regulatory T cells caused mouse models to lose protective immune function, leaving inflammatory effector T cells active.
- ▪Antibiotic treatment that depleted most gut bacteria in Wdr82-deficient mouse models prevented intestinal inflammation and stopped lethal autoimmune consequences.
- ▪Deleting the Wdr82 gene in mouse model T cells caused severe inflammation and autoimmunity in the intestine, heart, and lungs, eventually becoming lethal.
Asymmetric Wdr82 effects across T-Cell subtypes
- ▪Loss of Wdr82 deprived regulatory T cells of protective function while inflammatory effector T cells retained their activity, challenging assumptions of uniform gene expression.
- ▪St. Jude researchers stated that genetic variations previously dismissed as irrelevant to T cells as a whole may selectively cause disease in specific T-cell subtypes.
Implications for autoimmune research
- ▪Analyzing general gene-regulatory pathways in specific cell populations may improve understanding of inflammatory bowel disease, food allergies, and incurable autoimmune conditions.
- ▪Scientists have frequently excluded broadly expressed genes from autoimmune disease analyses based on the assumption that such genes function identically across all cell types.
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