The cells that stop the body attacking itself

Your immune system is an army trained to attack anything that does not belong, like germs and viruses. But there is a problem. A few of its soldiers are trained, by accident, to attack your own body.

To keep the peace, the body has a special group of cells whose only job is to hold those soldiers back. They work like security guards. When a soldier cell is about to attack your own healthy tissue, a guard steps in front of it and tells it to stand down.

Every guard is built by the same instruction, a gene called FOXP3. FOXP3 is the master switch that tells a young cell to grow up into a guard instead of a soldier. Three scientists worked out who the guards are and which switch makes them.

Your immune system has to solve a hard problem. It needs T cells aggressive enough to destroy infected or foreign cells, yet it must not let those same cells attack the body's own tissue. The first defence is central tolerance: as T cells mature in the thymus, those that react strongly to the body's own molecules are deleted before they ever reach the bloodstream.

Central tolerance is not perfect. Some self-reactive T cells slip through and circulate in the body. For decades the textbook view held that deletion in the thymus was the whole story. In 1995 Shimon Sakaguchi showed it was not.

What actually makes a cell a regulatory T cell stayed unclear until a separate line of work cracked it. A mutant mouse strain called scurfy died young from a runaway autoimmune attack. In 2001 Mary Brunkow and Fred Ramsdell traced the defect to a single damaged gene, which they named Foxp3. They went further and showed that mutations in the human version of the gene cause IPEX, a rare and deadly autoimmune disease in children.

Two years later Sakaguchi tied the threads together. He proved that the Foxp3 gene governs the development of the very cells he had found in 1995. FOXP3 is the master switch: turn it on in a developing T cell and the cell becomes a regulatory T cell, a guard rather than a fighter.

Immune tolerance is built in two layers. Central tolerance operates in the thymus, where developing thymocytes that bind self-peptide-MHC too strongly are removed by clonal deletion. This purges most dangerous clones, but the process is leaky, and self-reactive T cells routinely escape into the periphery. Peripheral tolerance is the set of mechanisms that restrains those escapees in the tissues and lymph nodes. The 2025 prize recognises the discovery that a dedicated cell lineage enforces it.

The lineage still needed a molecular definition, and that came from genetics. The scurfy mouse, an X-linked mutant, dies of a fatal CD4+ T cell lymphoproliferative and inflammatory disorder. In 2001 Brunkow, Ramsdell and colleagues mapped the defect to a novel forkhead/winged-helix gene they named Foxp3 (the protein, scurfin). In parallel, mutations in human FOXP3 were shown to cause IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), the human counterpart of scurfy.

FOXP3+ regulatory T cells suppress through several routes: consuming local IL-2, secreting inhibitory cytokines such as IL-10 and TGF-beta, and engaging CTLA-4 to dampen antigen-presenting cells. The clinical stakes run in both directions. Too little regulatory T cell activity permits autoimmunity, as in IPEX, type 1 diabetes and inflammatory bowel disease. Too much shields a target from the immune system, which is exactly how many tumours evade attack, since regulatory T cells inside a tumour blunt the anti-cancer response.