How the thymus shaped immunology The function of the thymus was discovered by Jacques Miller in 1961 and laid a foundation for immunology and modern medicine. Until that time, researchers mistakenly believed the thymus merely represented a remnant of defunct lymph tissue, something of an immune cell graveyard. In a Review, Miller recounts the seminal experiments and conceptual thinking that led to uncovering the critical function of the thymus and provides insights that can be learned from those early days. How knowledge of thymus function subsequently spawned the field of T cell biology and the impact it has had on immune cell interactions, vaccination, cancer immunotherapy, and the microbiome are also discussed. Science, this issue p. eaba2429 BACKGROUND Until the 1960s, the thymus had long remained an enigmatic organ with no known function or was considered to be just a “graveyard” for dying lymphocytes. By contrast, the circulating small lymphocytes found in blood and lymph had been shown in the late 1950s to be long-lived cells able to initiate an immune response when appropriately stimulated by antigen. However, although the thymus was known to be populated with lymphocytes, immunologists had not attributed any immune function to the organ. There were many reasons for this. For example, the cytological hallmarks of an immune response, such as the presence of plasma cells and germinal centers, were not seen in the thymus of healthy animals even after extensive immunization. Thymus lymphocytes, unlike lymphocytes from blood and lymphoid tissues, were unable to mount an immune response on transfer to immunocompromised recipients. Furthermore, thymectomy, which had always been performed in adult animals, was not associated with any immune defects. ADVANCES In 1961, thymectomy was performed in mice during the immediate neonatal period and revealed the critically important function of the thymus in enabling the development of the immune system. Neonatally thymectomized (NTx) mice were highly susceptible to intercurrent infections, deficient in lymphocytes, unable to reject foreign skin grafts or produce antibody to some (though not all) antigens, and prone to developing certain tumors. There was no major immune defect after adult thymectomy unless the lymphoid tissues had been damaged by total body irradiation. Implanting thymus tissue into NTx mice or irradiated adult thymectomized mice restored immune function. When the thymus graft was taken from a foreign strain, the thymectomized recipients were found to be specifically tolerant of the histocompatibility antigens of the donor. This implied that the thymus was responsible not only for the normal development of immune functions but also for imposing tolerance to the body’s own tissues. The thymus was shown to seed the lymphoid system with T lymphocytes that migrated to certain discrete areas of the lymphoid tissues and recirculated from the blood through lymphoid tissues, lymph, and back to the bloodstream. T cells exiting the thymus were found to be responsible for killing infected cells and for rejecting foreign tissue grafts. Therefore, T cells could soon be subdivided into subsets based on function, cell surface markers, and secreted products or interleukins. Thymus lymphoid stem cells were subsequently identified, and the epithelial and dendritic cells in the thymus were shown to greatly influence T cell development. They were able to educate T cells to recognize a great diversity of peptide antigens bound to the body’s own markers, major histocompatibility complex molecules, but purged any T cells that strongly reacted against the body’s own self-components. The use of irradiated adult thymectomized mice showed that T cells were not the precursors of antibody-forming cells but were essential to help, through some type of collaboration, other lymphocytes originating in bone marrow (B cells) to respond to antigen by producing antibody. OUTLOOK The discovery of thymus function and of T and B cell collaboration was a major immunological milestone because it not only opened up the field of immune cell interactions but also changed the course of immunology and medicine. It promoted the need for all immune phenomena, for example, memory, tolerance, autoimmunity, and immunodeficiency, as well as inflammatory and immunopathological disease conditions, to be reassessed in terms of the role played by the two distinct sets of lymphocytes and their subsets. We now know that T cells are involved in the entire spectrum of tissue physiology and pathology and even in situations not considered to be bona fide immunological conditions, such as tissue repair, dysbiosis, eclampsia, senescence, and cancer. Origin and migration of T and B cells. Hemopoietic stem cells originating in the yolk sac, fetal liver, or bone marrow migrate through the blood to the thymus, where they differentiate into T lymphocytes. Others differentiate within the bone marrow in mammals, or the bursa of Fabricius in birds, to produce B cells. Mature T and B cells circulate in the blood and lymph and colonize the T and B cell compartments of the lymphoid tissues. Reprinted with permission from the Royal Society, London The lymphoid system is intimately involved in immunological processes. The small lymphocyte that circulates through blood into lymphoid tissues, then through the lymph and back to the blood through the thoracic duct, is able to initiate immune responses after appropriate stimulation by antigen. However, the lymphocytes found in the thymus are deficient in this ability despite the fact that the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological faculty. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and in other lymphoid tissues. They become “educated” in the thymus to recognize a great diversity of peptide antigens bound to the body’s own marker antigen, the major histocompatibility complex, but they are purged if they strongly react against their own self-components. Lymphocytes differentiate to become various T cell subsets and then exit through the bloodstream to populate certain areas of the lymphoid system as peripheral T lymphocytes with distinct markers and immune functions.

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胸腺的功能及其对现代医学的影响

胸腺如何塑造免疫学 胸腺的功能由雅克·米勒于 1961 年发现，为免疫学和现代医学奠定了基础。在那之前，研究人员错误地认为胸腺仅代表失效的淋巴组织的残余物，某种免疫细胞墓地。在一篇评论中，米勒讲述了导致揭示胸腺关键功能的开创性实验和概念思维，并提供了可以从早期学习的见解。还讨论了胸腺功能的知识如何随后催生了 T 细胞生物学领域，以及它对免疫细胞相互作用、疫苗接种、癌症免疫疗法和微生物组的影响。科学，这个问题 p。eaba2429 背景 直到 1960 年代，胸腺长期以来一直是一个没有已知功能的神秘器官，或者被认为只是垂死淋巴细胞的“墓地”。相比之下，在 1950 年代后期发现的血液和淋巴液中的循环小淋巴细胞是长寿细胞，当受到抗原的适当刺激时，能够启动免疫反应。然而，尽管已知胸腺中充满了淋巴细胞，但免疫学家并未将任何免疫功能归因于该器官。这有很多原因。例如，即使经过广泛的免疫接种，在健康动物的胸腺中也没有观察到免疫反应的细胞学特征，例如浆细胞和生发中心的存在。胸腺淋巴细胞与血液和淋巴组织的淋巴细胞不同，无法在转移到免疫功能低下的受者身上时产生免疫反应。此外，一直在成年动物中进行的胸腺切除术与任何免疫缺陷无关。进展 1961 年，在刚出生的小鼠身上进行了胸腺切除术，揭示了胸腺在促进免疫系统发育方面的极其重要的功能。新生儿胸腺切除 (NTx) 小鼠对并发感染高度敏感，缺乏淋巴细胞，无法排斥外来皮肤移植物或产生针对某些（尽管不是全部）抗原的抗体，并且容易发生某些肿瘤。除非淋巴组织被全身照射损伤，否则成人胸腺切除术后没有重大免疫缺陷。将胸腺组织植入 NTx 小鼠或经照射的成年胸腺切除小鼠体内，可以恢复免疫功能。当胸腺移植物取自外来菌株时，发现切除胸腺的受体对供体的组织相容性抗原具有特异性耐受性。这意味着胸腺不仅负责免疫功能的正常发育，还负责对身体自身组织产生耐受性。胸腺被证明为淋巴系统提供了 T 淋巴细胞的种子，这些 T 淋巴细胞迁移到淋巴组织的某些离散区域，并从血液中通过淋巴组织、淋巴液再循环，然后回到血流。发现离开胸腺的 T 细胞负责杀死受感染的细胞和排斥外来组织移植物。所以，根据功能、细胞表面标志物和分泌产物或白细胞介素，T 细胞很快就会被细分为亚群。随后鉴定了胸腺淋巴样干细胞，胸腺中的上皮细胞和树突细胞显示出极大地影响了 T 细胞的发育。他们能够训练 T 细胞识别与身体自身标志物、主要组织相容性复合物分子结合的多种肽抗原，但清除了任何与身体自身成分发生强烈反应的 T 细胞。使用辐照的成年胸腺切除小鼠表明，T 细胞不是抗体形成细胞的前体，但对于通过某种类型的合作帮助其他源自骨髓的淋巴细胞（B 细胞）通过产生抗体对抗原做出反应至关重要。展望 胸腺功能和 T 细胞和 B 细胞协同作用的发现是一个重要的免疫学里程碑，因为它不仅开辟了免疫细胞相互作用的领域，而且改变了免疫学和医学的进程。它促进了对所有免疫现象的需要，例如，记忆、耐受、自身免疫和免疫缺陷，以及炎症和免疫病理疾病，需要根据两组不同的淋巴细胞及其亚群所发挥的作用进行重新评估。我们现在知道 T 细胞涉及整个组织生理学和病理学，甚至在不被认为是真正的免疫条件的情况下，如组织修复、生态失调、子痫、衰老和癌症。T 和 B 细胞的起源和迁移。源自卵黄囊的造血干细胞，胎儿肝脏或骨髓通过血液迁移到胸腺，在那里它们分化为 T 淋巴细胞。其他细胞在哺乳动物的骨髓或鸟类的法氏囊中分化，以产生 B 细胞。成熟的 T 和 B 细胞在血液和淋巴中循环，并定植在淋巴组织的 T 和 B 细胞区室中。经伦敦皇家学会许可转载 淋巴系统与免疫过程密切相关。通过血液循环进入淋巴组织，然后通过淋巴并通过胸导管返回血液的小淋巴细胞能够在适当的抗原刺激后启动免疫反应。然而，尽管胸腺在淋巴细胞的产生和确保免疫功能的正常发育方面起着核心作用，但在胸腺中发现的淋巴细胞缺乏这种能力。在胚胎发生过程中，淋巴细胞先存在于胸腺中，然后才能在循环和其他淋巴组织中被识别出来。它们在胸腺中“受教育”以识别与身体自身标记抗原（主要组织相容性复合体）结合的多种肽抗原，但如果它们与自身成分发生强烈反应，则会被清除。淋巴细胞分化为各种 T 细胞亚群，然后通过血流排出，作为具有不同标记和免疫功能的外周 T 淋巴细胞进入淋巴系统的某些区域。