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

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.

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 bodys 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 bodys own markers, major histocompatibility complex molecules, but purged any T cells that strongly reacted against the bodys 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.

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.

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.

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 bodys 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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The function of the thymus and its impact on modern medicine - Science

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