During infections, the immune system needs to distinguish foreign molecules from invading bacteria and viruses from molecules that are made by cells of the body. If it can’t, the immune system can mistakenly attack its own cells, causing lasting damage to tissue and potential long-term disease.
New research from the University of Chicago shows how a specially trained population of immune cells “keeps the peace” by preventing other immune cells from attacking their own.
The study, published in Science, provides a better understanding of immune regulation during infection and could provide a foundation for interventions to prevent or reverse autoimmune diseases.
Peace patrol
Several different groups of white blood cells help coordinate immune responses.
Some, known as dendritic cells, take up proteins from foreign pathogens, chop them up into peptides called antigens, and display them on their surface. Another group, known as helper T cells, inspects the peptides presented by dendritic cells.
If the peptides are foreign antigens, the T cells expand in numbers and transform into an activated state to eradicate the pathogen. However, if the dendritic cell is carrying a “self-peptide,” or peptides from the body’s own tissue, the T cells are supposed to lay off.
But sometimes the helper T cells don’t properly distinguish between foreign peptide antigens and self-peptides and go on the attack no matter what. This causes symptoms of autoimmune disease.
To prevent this from happening, another group called Treg cells—short for CD4+ regulatory T cells—are supposed to intervene and prevent friendly fire.
“You can think of them as peacekeeper cells,” said Pete Savage, professor of pathology at UChicago and senior author of the new study.
Tregs obviously do their job well most of the time, but Savage said it's never been clear to scientists how they know when to intervene and prevent helper T cells from starting an autoimmune response, and when to hold back and let them fight an infection.
So Savage and his team, led by David Klawon, a former graduate student in his lab who is now a postdoctoral fellow at MIT, wanted to explore this property of the immune system, known in the field as self-nonself discrimination.
Self sabotage
When Treg cells are produced, they are trained to recognize specific peptides, including self-peptides from the body. When dendritic cells present a self-peptide, the peacekeeper Treg cells trained to spot them intervene to stop helper T cells from getting triggered.
Each Treg cell specializes in specific peptides. Working with mice, the researchers experimentally depleted Treg cells that specialize in a particular self-peptide from the prostate.
In healthy mice without infection, this change did not trigger autoimmunity. But when the researchers infected mice with a bacterium that expressed the prostate self-peptide, T helper cells were triggered—and without Treg cells to stop them, introduced autoimmunity to the prostate.
However, this alteration did not impair the ability of helper T cells to control the bacterial infection by responding to foreign peptides.
“It's like a doppelganger population of T cells. The CD4 helper cells that could induce disease by attacking the self share an equivalent, matched population of these peacekeeper Treg cells,” Savage said. “When we removed Treg cells reactive to a single self-peptide, the T helper cells reactive to that self-peptide were no longer controlled, and they induced autoimmunity.”
Specificity matters
The root causes of autoimmune disease are a complex interaction of genetics, environment, lifestyle and the immune system.
Classic, conventional thinking in the immunology field promoted the idea that the immune system establishes self-nonself discrimination by purging the body of helper T cells that are reactive to self-peptides, thereby preventing autoimmunity.
But Savage said this study shows that purging is inefficient, and that specificity matching by Treg cells may be equally as important.
“The idea is that specificity matters, and for a fully healthy immune system, you need to have a good collection of these doppelganger Treg cells,” he said. As long as the immune system generates enough matched Treg cells, they can prevent autoimmune responses without impacting responses to infections.
“It's like flipping the idea of self-nonself discrimination upside down. Instead of having to delete all helper T cells reactive to self-antigens, you simply generate enough of these Treg peacekeeper cells instead,” Savage said.
For the study, Savage and Klawon worked in close collaboration with co-first author Nicole Pagane, a graduate student at MIT, as well as co-corresponding authors Harikesh Wong at the Ragon Institute of the Massachusetts General Hospital, MIT and Harvard University, and Ron Germain at the National Institutes of Health.
Additional authors from UChicago included Matthew T. Walker, Nicole K. Ganci, Christine H. Miller, Donald M. Rodriguez, Ryan K. Duncombe and Erin J. Adams.
Citation: "Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection." Klawon et al, Science, Feb. 27, 2025.
Funding: National Institute of Allergy and Infectious Diseases, the Chicago Biomedical Consortium, the Institute for Translational Medicine, the National Institutes of Health, the U.S. Department of Energy, and the Mark and Lisa Schwartz Artificial Intelligence and Machine Learning Initiative.
—Adapted from an article first published by the Biological Sciences Division.
