COMPASS pathway enables regulatory T cells to prevent devastating autoimmune responses to gut bacteria

Trillions of bacteria live in the human gut without triggering an immune response. Scientists at St. Jude Children’s Research Hospital have now discovered a gene-regulatory pathway that helps maintain this delicate balance. In a study published in Science Advances, they show that regulatory T cells, a type of immune cell, co-opt a well-known general gene expression pathway called COMPASS to suppress inappropriate immune responses and prevent lethal inflammation and autoimmunity.

Within the body, immune cells distinguish between self and nonself, eliminating that which they consider nonself, such as viruses and bacteria. In the gut, this is complicated by the presence of the intestinal microbiota, a community of beneficial bacteria that live there. Regulatory T cells stop other immune cells from inappropriately reacting to these bacteria, though the genetic factors that govern the process were poorly understood.

To identify those factors, the St. Jude scientists used a CRISPR screen, uncovering that the gene Wdr82, a key component of the gene activation pathway COMPASS, plays an essential role in enabling regulatory T cells to maintain intestinal immune tolerance.

“We found that under normal conditions, the COMPASS pathway enables regulatory T cells to prevent inflammation and autoimmunity in the intestine,” said corresponding author Yongqiang Feng, Ph.D., St. Jude Department of Immunology. “When this pathway is compromised, the immune system no longer recognizes these bacteria as harmless but rather treats them as inflammatory triggers.”

When the researchers deleted Wdr82 in T cells in mouse models, severe inflammation and autoimmunity developed in the intestine and, to a lesser extent, in the heart and lungs, eventually becoming lethal.

Introducing functional regulatory T cells with intact Wdr82 to these models reversed the disease process and prevented death. Similarly, antibiotic treatment, which depleted most of the gut bacteria, prevented inflammation and stopped its catastrophic consequences.

“Our results suggest that regulatory T cells with defects in the COMPASS pathway cannot act as a protective barrier between gut bacteria and the inflammatory responses of other immune cells,” Feng said.

Shared pathway with a specialized role sets a new precedent

Although Wdr82 is expressed across T-cell types, its loss did not affect all subtypes equally. Regulatory T cells lost their protective function, while inflammatory effector T cells retained their activity. The findings reveal that a broadly used gene-regulatory pathway can have a specialized role in maintaining immune balance, challenging the prevailing assumption that such pathways function similarly across cell types.

“As a field, we’ve assumed that the general gene expression regulators like Wdr82 have universal functions in every type of T cell,” Feng said. “Our study introduces a new concept: General regulatory factors can have asymmetric effects across T-cell subtypes, performing specialized roles in particular immunological processes.”

This discovery sets a precedent that asymmetry may be hiding sources of unexplained autoimmunity, as scientists have often excluded broadly expressed genes from their analyses, assuming they function similarly in all cell types.

Examining how general gene-regulatory pathways operate in specific immune cell populations may help researchers reveal previously overlooked mechanisms, leading to a better understanding of inflammatory bowel disease, food allergies and other as-yet incurable autoimmune conditions.

“We are excited because genetic variations found in patients with autoimmune diseases may have been dismissed as potential causes because they appeared to be irrelevant to T cells as a whole,” Feng said.

“Now, we can begin looking back at these variants to determine whether they selectively affect a particular T-cell subtype, understand how they cause disease and then open the path to creating novel treatments.”

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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