How Regulatory T Cells Keep The Body From Attacking Itself

The ideal immune system targets invading bacteria and viruses but does not attack our own cells. The ability for the immune system to differentiate our body’s cells from invaders is called “self-nonself discrimination.” 

During an immune response, cells called dendritic cells take proteins from invading cells and turn them into small fragments called antigens. These cells add the antigens on their cell surface where they can be recognized by a type of immune cells called T cells. If the antigens belong to invading cells, helper T cells become activated to target the invaders. However, if the dendritic cell displays a self-antigen, the helper T cells shouldn’t respond. Immune cells called regulatory T cells are a critical player in preventing self-attack, but it’s been unclear how regulatory T cells know when to prevent the immune system from responding.

In a study from the University of Chicago, researchers examined how this happens by looking at regulatory T cells that recognize the same self-antigen that helper T cells do. These T cells are called “matched.” They designed a study where they deleted regulatory T cells that recognize a self-peptide in the prostate. Without bacterial infection, there was no autoimmunity. When the researchers infected mice with a bacterium that possessed a prostate self-peptide, they saw that the bacteria triggered an autoimmune response to the prostate because there weren’t any prostate-specific regulatory T cells to stop it. Because the bacterium also expresses other peptides, it can still trigger an immune response against the bacteria via bacteria-specific peptides.

This research presents a complementary mechanism of self-tolerance beyond the traditional view that autoimmunity is prevented solely by inactivating self-reactive helper T cells.

Citation: 

Klawon, D.J., et al. (2025). Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection. Science, 387(6740):eadk3248. https://doi.org/10.1126/science.adk3248