How transcription factor dynamics control immune responses

T regulatory cells (Tregs) are the peacekeepers of the immune system. They keep the other immune cells in line by preventing them from overreacting to potential threats and responding when appropriate. However, research is still lacking on how these cells themselves are regulated.

But now, researchers at St. Jude Children’s Research Hospital, led by immunologist Yongqiang Feng, discovered that the transcription factor forkhead box P3 (Foxp3) attaches to different areas of the genome and binds to different partners depending on the cell’s inflammatory status (1). Understanding how the body regulates Tregs in different immunological contexts could provide new insights into treatment options for conditions ranging from autoimmune diseases to cancers.

“This population of Treg cells is really essential to keep us healthy, keep us from being mystically attacked about our T cells, [which] we call the killer cells,” said Feng. “We are living together with the killers in our bodies, … so the T[reg] cells know the balance.”

Scientists have known for a long time that Foxp3 acts as a transcription factor and controls Treg gene expression by binding to specific DNA sequences. Foxp3 regulation gives Tregs their immunosuppressive function: Foxp3-deficient mice succumb to lethal autoimmune diseases, while human mutations in the Foxp3 gene cause the fatal autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (2). But how exactly Foxp3 does this under different immunological conditions — for example, during inflammation or in a normal state — was unknown.

To better understand how Foxp3 interacted with DNA and regulated Treg gene expression, the researchers used chromatin accessibility assays including CUT&Tag-seq and CUT&RUN-seq to determine precisely where in the genome Foxp3 binds. They found that Foxp3 binds to different sites depending on whether the Tregs were in a resting or activated state, indicating that the transcription factor’s function adapted to the cellular inflammatory conditions.

“This protein actually is working in a very dynamic way,” said Feng. “Instead of waiting for signals to come in, the signal [is] actually driven by the environment the cells [are] exposed to.”

Foxp3 is known to regulate gene expression with a complex network of proteins (3). These partner proteins, induced by specific cellular signals, act as cofactors, guiding Foxp3 to its target genes. This mechanism allows Foxp3 to be adaptable and respond to signals from the immune system.

To uncover the identity of these protein partners in different immunological contexts, Feng and his team used proximity proteomics, a technique that identifies proteins physically interacting with a protein of interest. When they exposed Tregs to IL-2 or T cell receptor stimulation, the proteins that interacted with Foxp3 differed, revealing that certain cofactors are vital in specific immunological contexts.

Identifying how gene expression in Tregs is controlled opens new research avenues for inflammatory diseases. For example, in autoimmune diseases, where the immune system attacks the body's own cells, boosting the activity of regulatory T cells could help restore immune balance. Strategies to inhibit their function could be explored in cancer, where these cells can suppress anti-tumor immune responses.

“It is important to understand how Foxp3 works in these different contexts because then eventually you can target specific contexts,” said Dipayan Rudra, an immunologist from ShanghaiTech University who was not involved in this study. “With the advent of new technologies, now it is possible to ask these questions, and they have done a wonderful job in asking [them].”

Feng’s group plans to explore other cell types in the adaptive immune response critical in immune tolerance and recognition of host cells. They hope a greater understanding of how the body maintains a steady state of inflammation can contribute to our understanding of disease processes.

“This dynamic model, we think this is really exciting, and now we actually have provided a new angle to understand how these cells work. I don't think we stop there,” said Feng. “We need to rethink the knowledge we’ve been building [over] the last 20 years.”

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