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Regulatory T cells: maintainers of peripheral immune tolerance

ZHANG Yu^*

Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Abstract

On October 5th, the 2025 Nobel Prize in Physiology or Medicine was announced. Japanese scientist Shimon Sakaguchi, American scientists Mary E. Brunkow, and Fred Ramsdell were awarded this prize in recognition of their outstanding contributions to the study of peripheral immune tolerance mechanisms. Nobel Committee Chair Olle Kämpe said, "Their discovery is crucial, not only deepening our understanding of immune system function, but also explaining why most individuals do not suffer from severe autoimmune diseases. This is the third time in the past decade that immunologists have won this crown. The previous two were Hoffman, Beutler, and Steinman, who won the award for discovering Toll like receptors and dendritic cells in 2011, and Allison and Honjo, who won the award for inventing immune checkpoint blockade therapy in 2018. How the immune system can effectively eliminate foreign antigens while maintaining tolerance to its own antigens is one of the core issues in immunology. In the mid-20th century, Burnet proposed the "clonal selection" theory, which is regarded as the cornerstone of modern immunology, and was awarded the Nobel Prize in 1960 for it. According to this theory, self reactive lymphocytes are cleared through negative selection during development, thereby establishing tolerance to self antigens. Given that negative selection occurs in the central immune organs (thymus and bone marrow), this tolerance mechanism is called "central tolerance". However, negative selection is not perfect, as there are always some self reactive lymphocytes that escape to the periphery. However, severe autoimmunity rarely occurs. Therefore, there must also be some mechanism in the periphery to maintain non responsiveness to self antigens. In 1995, Shigefumi Sakaguchi first reported a group of CD4⁺CD25⁺ T cells with immunosuppressive activity, which he named regulatory T cells (Tregs). Subsequently, Brunkow and Ramsdell cloned the transcription factor Foxp3, which is crucial for the development and function of this group of cells, confirming at the molecular level that Tregs are a unique subset of T cells. More importantly, the mutation of this gene leads to severe autoimmune diseases in both mice and humans, demonstrating its indispensable role in maintaining peripheral immune tolerance.

Received: 　　Accepted:

Corresponding author: 张毓　　E-mail:

DOI: 10.13294/j.aps.2025.0086

Citing This Article：

ZHANG Yu. Regulatory T cells: maintainers of peripheral immune tolerance. Acta Physiol Sin 2025; 77 (5): 753-756 (in Chinese with English abstract).