Scientists at St. Jude Children’s Research Hospital in the United States have identified a gene-regulatory mechanism that helps regulatory T cells (Tregs) maintain immune tolerance to the trillions of bacteria inhabiting the gut. Published in Science Advances, the study identifies the COMPASS pathway and its component WDR82 as key regulators of Treg function in maintaining intestinal immune homeostasis. The findings offer new insights into how disruptions in this pathway can trigger microbiota-driven intestinal inflammation and may help researchers better understand inflammatory bowel disease and other immune-mediated disorders.
The intestinal immune system faces a continuous challenge in distinguishing harmful microorganisms from beneficial bacteria that constitute the gut microbiota. Although immune responses are essential for eliminating pathogens, excessive activation against harmless intestinal microorganisms can lead to chronic inflammation and tissue damage. Tregs help maintain this delicate balance by suppressing inappropriate immune responses and promoting tolerance toward resident microorganisms.
Despite their established role in immune regulation, the genetic mechanisms that enable Tregs to sustain intestinal tolerance have remained incompletely understood. To investigate these mechanisms, researchers conducted a CRISPR-based genetic screen to identify factors essential for Treg function. The analysis identified Wdr82, a component of the COMPASS complex, as a critical regulator of intestinal immune homeostasis.
COMPASS is an epigenetic regulatory complex involved in controlling gene expression through histone modifications, particularly histone H3 lysine 4 trimethylation (H3K4me3), which is associated with transcriptionally active genes. Although components of this complex are widely expressed across different cell types, the researchers found that Wdr82 has a particularly important role in maintaining the development and suppressive function of Tregs.
Further investigations revealed that Wdr82/COMPASS supports the expression of Foxp3, a transcription factor essential for Treg development and function. The pathway also helps maintain chromatin accessibility at Treg-associated genes while restricting inflammatory gene-expression programs. These findings establish a link between epigenetic regulation and the ability of Tregs to preserve their immunosuppressive properties.
To determine the physiological importance of this mechanism, the researchers deleted Wdr82 specifically in T cells in mouse models. The animals subsequently developed severe intestinal inflammation accompanied by autoimmune manifestations in other organs, including the heart and lungs. The inflammatory disease progressively worsened and eventually became fatal. Although Wdr82 deficiency affected T-cell activation more broadly, its consequences were particularly pronounced in Tregs. Loss of Wdr82 compromised their ability to suppress inflammatory immune responses, disrupting the balance between immune activation and regulation.
The researchers further demonstrated the importance of Wdr82 by introducing functional Tregs containing intact Wdr82 into the affected animals. This intervention reversed the inflammatory disease, providing evidence that defective Treg function was a major contributor to the observed pathology.
To investigate whether intestinal bacteria were responsible for triggering inflammation, the researchers treated the animals with antibiotics to substantially reduce their gut microbiota. This intervention prevented severe intestinal inflammation and protected the animals from the otherwise fatal consequences of Wdr82 deficiency. The findings indicate that intestinal microorganisms become major drivers of inflammatory disease when Treg-mediated immune tolerance is impaired.
The study also challenges the conventional understanding that widely expressed epigenetic regulators perform largely similar functions across immune cell populations. The pronounced dependence of Tregs on Wdr82 suggests that broadly expressed gene-regulatory factors can have specialized roles in maintaining immune homeostasis.
These findings offer a new perspective on how the immune system coexists with beneficial intestinal microorganisms without initiating destructive inflammatory responses. They also suggest that abnormalities in epigenetic regulatory pathways may contribute to autoimmune and inflammatory diseases by selectively compromising Treg function. Although further studies are needed to establish the relevance of these findings in humans, identifying Wdr82/COMPASS as a key regulator of intestinal immune tolerance may open new avenues for investigating therapeutic strategies aimed at restoring Treg function in inflammatory bowel disease and other immune-mediated conditions.
Reference
- Huang W, Li J, He M, Xu B, Rosikiewicz W, Hao X, et al. Wdr82-COMPASS coordinates Foxp3 and TCR signaling to sustain Treg cell control of microbiota-driven intestinal inflammation. Sci Adv. 2026;12(44):eah9188.