The 2025 Nobel Prize in Physiology or Medicine has recognised discoveries that transformed the scientific understanding of autoimmune regulation. Today, researchers are exploring these conditions’ genetic, molecular, and environmental determinants, paving the way for early diagnoses and targeted interventions. An important chunk of this advance is owed to the work of Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi, who established the role of regulatory T-cells (Tregs) and the transcription factor FOXP3. In the 1990s, immunologists had already defined the deletion of self-reactive T-cells during maturation, yet this process could not account for the persistence of autoreactive T-cells in healthy individuals. Sakaguchi figured that an additional mechanism must operate in the periphery. In 1995, his team identified a subset of CD4⁺ T-cells that, when they were removed from mice, led to multiple autoimmune disorders, while restoring the cells prevented disease. Next, Brunkow and Ramsdell, then at Celltech Chiroscience, found that male scurfy mice developed severe multi-organ autoimmunity and died within weeks of birth. They were able to narrow the mutation to the X chromosome, identifying an insertion in the DNA that truncated a previously unknown gene. They named it FOXP3, and found that losing it led to immune collapse. Soon, clinical collaborations reported mutations in FOXP3 in boys with a lethal autoimmune disorder. These findings together established that self-tolerance rested on a molecular switch governing the differentiation and maintenance of Tregs.
Today, in autoimmune diseases, experimental treatments aim to expand or stabilise Tregs. Early clinical trials have shown that reinforcing this cell population can mitigate harmful immune activation without broad immunosuppression. In transplantation, engineered Tregs are being infused to improve graft acceptance. In cancer, researchers are exploring selective depletion or reprogramming of tumour-associated Tregs to enhance immunity without triggering autoimmunity. Beyond therapy, the conceptual shift brought on by the laureates’ work has redefined the immune system: from an on/off apparatus to a dynamic ecosystem of activation and restraint. That Brunkow and Ramsdell conducted their work within industry also underscores how private sector research can yield significant discoveries. But even now, some immunologists caution against underestimating the field’s incremental nature. In a testament to the broader landscape including overlapping layers of control rather than a single molecular pathway, researchers face several obstacles to translating what they know to safe, scalable therapies. Cell-based therapies’ high cost has also accentuated inequities in access, creating ethical and policy challenges.
