How the thymus shaped immunology
The function of the thymus gland was discovered by Jacques Miller in 1961 and laid the foundation for immunology and modern medicine. Up until that point, researchers mistakenly believed that the thymus was just a remnant of dead lymphoid tissue, something like a graveyard for immune cells. In an essay, Miller recounts the groundbreaking experiments and conceptual considerations that led to the discovery of the critical function of the thymus, and provides insights that can be learned from those early days. It also discusses how knowledge of thymic function later spawned the field of T-cell biology and what impact it had on immune cell interactions, vaccination, cancer immunotherapy, and the microbiome.
science, this edition p. eaba2429
Until the 1960s, the thymus had long remained a mysterious organ with no known function or was only considered a “graveyard” for dying lymphocytes. In contrast, in the late 1950s, the circulating small lymphocytes in the blood and lymph were shown to be long-lived cells that are capable of initiating an immune response when appropriately stimulated by antigens. Although the thymus gland was known to be colonized by lymphocytes, immunologists had not ascribed an immune function to the organ. There were many reasons for this. For example, the cytological features of an immune response, such as the presence of plasma cells and germinal centers, were not observed in the thymus of healthy animals even after extensive immunization. In contrast to lymphocytes from blood and lymph tissue, thymus lymphocytes were unable to elicit an immune response when transmitted to immunocompromised recipients. In addition, the thymectomy, which was always performed in adult animals, was not associated with immunodeficiency.
In 1961, thymectomy was performed in mice during the immediate neonatal period and demonstrated the critical role of the thymus in the development of the immune system. Neonatal thymectomized (NTx) mice were very susceptible to intercurrent infections, were deficient in lymphocytes, were unable to reject foreign skin grafts or produce antibodies to some (if not all) antigens, and were prone to developing certain tumors. There was no major immune deficiency after thymectomy in adults unless the lymphatic tissue was damaged by whole-body radiation. Implantation of thymic tissue in NTx mice or irradiated adult thymectomized mice restored immune function. When the thymus graft was removed from a foreign strain, the thymectomized recipients were found to be specifically tolerant of the donor’s histocompatibility antigens. This implied that the thymus gland was not only responsible for the normal development of immune functions, but also for tolerance to the body’s own tissues.
The thymus has been shown to colonize the lymphatic system with T lymphocytes that migrated to certain discrete areas of the lymphatic tissue and were returned from the blood through lymphoid tissue, lymph and back into the bloodstream. It has been found that T cells leaving the thymus are responsible for killing infected cells and for rejecting foreign tissue grafts. Therefore, T cells could soon be divided into subsets based on function, cell surface markers, and secreted products or interleukins. Thymus lymphoid stem cells were then identified and the epithelial and dendritic cells in the thymus were shown to have a major impact on T cell development. They were able to train T cells to recognize a wide variety of peptide antigens bound to the body’s own markers, important histocompatibility complex molecules, but to purify any T cells that reacted strongly against the body’s own components. The use of irradiated adult thymectomized mice showed that T cells were not the precursors of antibody-producing cells, but were essential in helping other bone marrow lymphocytes (B cells), through some sort of cooperation, to respond to antigens through the Production of antibodies to respond.
The discovery of thymic function and T and B cell collaboration was an important immunological milestone as it not only opened up the field of immune cell interactions, but also changed the course of immunology and medicine. It promoted the need to reassess all immune phenomena, such as memory, tolerance, autoimmunity and immunodeficiency, as well as inflammatory and immunopathological disease states, in terms of the role of the two different groups of lymphocytes and their subgroups. Today we know that T cells are involved in the full spectrum of tissue physiology and pathology, and even in situations that are not considered to be in good faith immunological conditions, such as tissue repair, dysbiosis, eclampsia, senescence, and cancer.
The lymphatic system is closely involved in immunological processes. The small lymphocyte, which circulates through the blood into the lymph tissue, then through the lymph and back into the blood through the thoracic duct, is able to trigger immune responses after appropriate stimulation by antigens. However, the lymphocytes found in the thymus lack this ability, although the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological ability. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and other lymphoid tissues. They are “raised” in the thymus to recognize a wide variety of peptide antigens bound to the body’s own marker antigen, the major histocompatibility complex. However, they are purified when they react strongly against their own self components. Lymphocytes differentiate into various subsets of T cells and then exit through the bloodstream to populate certain areas of the lymphatic system as peripheral T lymphocytes with different markers and immune functions.