＃2-24E. 2025 Nobel prize in medicine - Defining the Sentinel: CD4+CD25+ T Cells and the Mechanism of Peripheral Tolerance (Lancet, 2025)

How does the immune system prevent catastrophic self-attack when the process of central tolerance in the thymus is inherently imperfect? This seminal study addressed the long-standing skepticism regarding the existence of active suppressor T cells. Researchers demonstrated that peripheral tolerance is actively maintained by a specific T cell subset. The study revealed that the physical removal of the approximately 10% of CD4+ T cells that also express the CD25 protein from healthy adult mice reliably induced severe autoimmune pathology. Conversely, transferring this population back resolved the symptoms. The most critical finding was the definitive identification and molecular definition of Regulatory T cells (Tregs) using the CD25 marker, thereby establishing the crucial mechanism of peripheral immune tolerance. For clinicians, this discovery is paramount as it underpins modern immunomodulatory strategies for diverse disorders, including rheumatoid arthritis, multiple sclerosis, and transplant rejection, offering pathways for targeted Treg-based cell therapies. However, physicians must remember that the initial proof of concept relied exclusively on an in vivo mouse model, requiring careful scrutiny when translating these findings directly to complex human immunological conditions.

Citation: Burki, Talha. The origins of tolerance: the 2025 Nobel prize in medicine. The Lancet, Volume 406, Issue 10513, 1714 - 1715.

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