Some of the issues causing progressive age-related failure of immune function result from the low rate of replacement of T cells in adults. T cells are created in the bone marrow but mature in the thymus, an organ that atrophies early in life in a process known as thymic involution. It then declines more slowly thereafter across the course of a life span. The level of activity in the thymus limits the rate at which new T cells arrive, and this in turn effectively puts a limit on the number of such cells supported by the body, and determines the rate of turnover in that population. As we age and are exposed to persistent pathogens, especially cytomegalovirus, ever more of the T cell population becomes specialized in ways that remove the ability to deal with new threats. A flood of new immune cells would help to restore the balance, and in recent years researchers have demonstrated that transplanting a young and active thymus into an old mouse does in fact restore measures of immune function, and extends life span as well. This is an indication that the research community should put more effort into regeneration and tissue engineering of the thymus as a way to partially reverse the age-related loss of immune function and the frailty that follows that loss.
The peripheral T cell compartment of aged individuals is characterized by great modifications, including a higher frequency of regulatory T cells (Treg). A tight balance between regulatory and conventional (Tconv) T cell subsets in the peripheral compartment, maintained stable throughout most of lifetime, is essential for preserving self-tolerance along with efficient immune responses. An excess of Treg cells, described for aged individuals, may critically contribute to their reported immunodeficiency. The relative contribution of alterations in thymic exportation versus changes in the homeostasis of the peripheral compartment affecting the Treg/Tconv lymphocytes balance is not yet clearly established, however. In this work, we investigated if quantitative changes in thymus emigration may alter the Treg/Tconv homeostasis regardless of the aging status of the peripheral compartment. We used two different protocols to modify the rate of thymus emigration: thymectomy of adult young (4-6 weeks old) mice and grafting of young thymus onto aged (18 months old) hosts. Alterations in Treg and Tconv peripheral frequencies following these protocols were investigated after 30 days.
Our results show that peripheral T cell homeostasis is promptly disturbed in the absence of the thymus. This disturbance was characterized by a preferential persistence of Treg cells that occurs independently of the age of either the T cells or the peripheral environment. The excess of Treg cells in aged mice is also very rapidly corrected by the grafting of a young functional thymus, supporting the hypothesis that thymus newly emigrated T cell populations, harboring an adequate physiological proportion of Treg/Tconv lymphocytes, are essential to compensate for an excess of peripheral Treg cell expansion or survival. It is also interesting to observe that the aged T cell precursors are fully able to colonize and differentiate in the young grafted thymus. These results suggest that the continuous output of the young grafted thymus, which is numerically much superior to the small number of cells emigrating from the aged host thymus, may contribute to normalize the peripheral proportions of Treg/Tconv cells. The aged peripheral compartment does not interfere with this homeostasis.
Our results, thus, highlight the importance of the thymus as a permanent source of emigrating populations of recently differentiated lymphocytes harboring an adequate, physiological proportion of Treg/Tconv lymphocytes, essential to keep the peripheral Treg cell balance, regardless of the aging status of the peripheral compartment. The immunosenescence associated with aging, in which an excess of Treg cells may impair the immune response to infections and tumors, highlights the relevance of understanding the peripheral Treg cell homeostasis for the development of adequate clinical strategies.