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调节性T细胞：外周免疫耐受的维护者

张毓^*

北京大学基础医学院免疫学系，北京 100191

摘要

10月5日，2025年度诺贝尔生理学或医学奖揭晓。日本科学家坂口志文(Shimon Sakaguchi)、美国科学家玛丽⋅E⋅布伦科(Mary E. Brunkow)与弗雷德⋅拉姆斯德尔(Fred Ramsdell)获颁该奖项，以表彰他们在外周免疫耐受机制研究方面的杰出贡献。诺贝尔委员会主席Olle Kämpe表示：“他们的发现至关重要，不仅深化了我们对免疫系统功能的理解，还解释了为什么多数个体不会患上严重的自身免疫疾病”。这是免疫学家在过去十余年里第三次摘得这项桂冠，前面的两次分别是，2011年因发现Toll样受体和树突状细胞而获奖的Hoffman、Beutler与Steinman，以及2018年因发明免疫检查点阻断疗法而获奖的Allison和Honjo。免疫系统如何在有效清除外来抗原的同时维持对自身抗原的耐受是免疫学的核心问题之一。上个世纪中叶，Burnet提出了被誉为现代免疫学基石的“克隆选择”学说，并因此获得了1960年度的诺贝尔奖。根据该学说，自身反应性淋巴细胞在发育过程中通过阴性选择得以清除，从而建立对自身抗原的耐受。鉴于阴性选择发生在中枢免疫器官(胸腺和骨髓)，这种耐受机制被称作“中枢耐受”。然而，阴性选择并非完美无缺，总有部分自身反应性淋巴细胞逃逸到外周。尽管如此，严重的自身免疫却很少发生。因此，外周也一定存在某种机制，维持对自身抗原的无反应性。1995年，坂口志文首先报道了一群具有免疫抑制活性的CD4⁺CD25⁺ T细胞，他将之命名为调节性T细胞(regulatory T cell, Treg)。随后，Brunkow和Ramsdell克隆了对这群细胞发育和功能至关重要的转录因子Foxp3，从分子层面证实了Treg是一个独特的T细胞亚群。更为重要的是，该基因的突变在小鼠和人类上均导致严重的自身免疫病，显示其在维持外周免疫耐受中不可或缺的作用。

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.

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通讯作者：张毓　　E-mail:

DOI: 10.13294/j.aps.2025.0086

引用本文：

张毓. 调节性T细胞：外周免疫耐受的维护者[J]. 生理学报 2025; 77 (5): 753-756.

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