Credit score: Immunity (2025). DOI: 10.1016/j.immuni.2025.10.020
The immune system faces a fragile balancing act: It have to be aggressive sufficient to combat infections and most cancers, but restrained sufficient to keep away from attacking the physique’s personal tissues.
Greater than twenty years in the past, researchers recognized a gene known as FOXP3 as enjoying a vital function in sustaining this steadiness and stopping autoimmune illness—work that garnered this 12 months’s Nobel Prize in Physiology or Drugs.
Now, scientists at Gladstone Institutes and UC San Francisco (UCSF) have mapped the intricate community of genetic switches that immune cells use to fine-tune ranges of FOXP3. Their findings, revealed in Immunity, have necessary implications for creating immune therapies and tackle a long-standing thriller about why this gene behaves in another way in people than in mice.
“FOXP3 is absolutely essential for regulating our immune systems,” says Alex Marson, MD, Ph.D., director of the Gladstone-UCSF Institute of Genomic Immunology, who led the research. “How it’s controlled is a fundamental question of immunology, and the detailed answer could offer clues to developing future therapies for autoimmune diseases or cancer.”
A seek for dimmer switches
The gene FOXP3 is lively in all regulatory T cells, which hold immune reactions in test. With out this gene, regulatory T cells can’t perform correctly and the immune system spirals uncontrolled, attacking the physique’s personal tissues. Individuals with mutations in FOXP3 develop uncommon and extreme autoimmune illnesses.
In mice, FOXP3 is just switched on in regulatory T cells. However in people, standard T cells—the inflammatory cells that combat infections—may also briefly activate FOXP3. This distinction has puzzled immunologists for years.
Within the new work, Marson’s lab used CRISPR-based gene silencing expertise to systematically check 15,000 websites within the DNA surrounding the gene FOXP3. They had been searching for genetic regulatory parts—close by stretches of DNA that act like dimmer switches, controlling when and the way a lot a gene is turned on or off.
By disrupting 1000’s of areas in each human and mouse regulatory and traditional T cells after which measuring results on FOXP3 ranges, the group recognized which close by DNA sequences management FOXP3.
“We essentially created a functional map of the entire FOXP3 control system,” says Jenny Umhoefer, Ph.D., a former postdoctoral fellow in Marson’s lab and first writer of the brand new paper.
A group of scientists—together with Jenny Umhoefer, seen right here—uncover potential clues for future autoimmunity and most cancers therapies by studying to fine-tune a gene that’s centrally concerned in regulating the immune system. Credit score: Michael Brief / Gladstone Institutes
Immune management panels
The experiments revealed that completely different human cell varieties have completely different management techniques for the gene FOXP3. In regulatory T cells, the place FOXP3 should stay consistently lively, a number of enhancers—DNA sequences that increase the degrees of a gene—work collectively to make sure the gene stays on. As a result of they work redundantly, disrupting simply a kind of enhancers had solely a small impact on FOXP3 ranges.
In standard T cells, solely two enhancers had been mapped. However the researchers additionally found an sudden repressor that acts as a brake on the FOXP3 gene.
“What we’re seeing is a sophisticated regulatory circuit,” Umhoefer says. “The cell has gas pedals and brakes, and it coordinates them to achieve precise control.”
To grasp not simply the place these genetic switches are positioned, but in addition what controls them, the group carried out a second huge CRISPR display. This time, they systematically disrupted almost 1,350 genes all through the genome to establish particular proteins that management FOXP3 ranges.
Then, working with Gladstone Affiliate Investigator Ansuman Satpathy, MD, Ph.D., the group used a method known as ChIP-seq to bodily map the place the proteins are positioned on the DNA in relation to the FOXP3 gene.
“This was a big step forward in developing ways to link the local regulatory elements with the proteins that actually bind to them,” says Satpathy, who can also be an affiliate professor within the Division of Pathology on the Stanford Faculty of Drugs. “No one had put together these tools in such a broad, systematic way before.”
A species thriller
Marson’s lab had initially hypothesized that in people, standard T cells could have an enhancer to activate FOXP3 that’s lacking in mice, explaining why the mouse cells by no means flip the gene on. Surprisingly, they discovered that standard T cells in mice have all the identical enhancer parts as people.
The distinction, the scientists realized, could lie within the repressor they found. In standard mouse T cells, this repressor retains FOXP3 consistently off. When the researchers used CRISPR to delete the repressor from the DNA of mice, the traditional T cells started to precise the FOXP3 gene like human cells.
“This was a striking result,” Marson says. “By removing a single repressive element, we could break the species difference and enable conventional T cells in mice to express FOXP3. This offers new hints as to how regulation of key genes might evolve across species.”
The findings level to the significance of learning gene regulation in human cells, and underscore the necessity to look broadly for repressors—not simply the extra widespread enhancer parts.
Precision cell engineering
The brand new research offers a basis for ongoing efforts to find and develop new therapies for a spread of illnesses. Armed with a full map of the completely different parts concerned in controlling the degrees of the FOXP3 gene, researchers can start to develop new methods of tweaking these ranges for immunotherapies.
Therapies for autoimmune illnesses, for example, could profit from elevated ranges of FOXP3, whereas therapies for most cancers may go higher with decrease FOXP3 exercise.
“There are enormous efforts right now to drug regulatory T cells, either to promote their activity or reduce it,” Marson says. “As we understand new aspects of the circuitry that distinguishes regulatory T cells from conventional cells, we can think about strategies to rationally manipulate it.”
Extra data:
Jennifer M. Umhoefer et al, FOXP3 expression will depend on cell-type-specific cis-regulatory parts and transcription issue circuitry, Immunity (2025). DOI: 10.1016/j.immuni.2025.10.020
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