The absolute requirement for the thymus in primary T cell development was established by Miller in the early 1960s [47] and remains a fundamental tenet of modern immunology. However, in contrast to its role in primary T cell development, obvious clinical immunodeficiency does not result when the thymus is removed after the 5th day of life in mice [47] and 6 months of age in humans [8]. This is due to the fact that peripheral T cell pools are maintained throughout life largely through a variety of thymic-independent mechanisms [62]. These include the prolonged life span of naive lymphocytes [19, 46, 63], slow turnover of some naive cells in response to low-affinity antigen [24, 25], antigen-driven expansion of naive and memory cells to cognate antigen [37, 53] and ongoing turnover of memory T cell pools via cytokinedependent pathways [35].

Thus, the current paradigm of T cell homeostasis holds that the thymus is extremely active in the fetal and perinatal period, during which time a sufficiently diverse repertoire of T cell receptor (TCR) specificities is generated to maintain the host throughout life. As long as there is no major pathologic event that results in depletion of the peripheral T cell pool, the role of the thymus in maintaining normal T cell populations in the adult is limited. However, in the setting of T cell depletion, such as is induced by HIV infection or cytotoxic chemotherapy, numerous studies have shown that thymic function is critical for restoring immune competence [41, 48]. When thymic function is limiting, as is common in clinical scenarios associated with T cell depletion,“homeostatic peripheral expansion” of residual mature T cells is the primary contributor to the regeneration of the T cell pool [5, 13, 40, 49, 67]. Such thymic-independent pathways are limited, both in terms of the quality and quantity of the T cells generated. Therefore, the development of new therapies that can be used to enhance thymic regenerative pathways in humans with T cell depletion are greatly needed.