Parallels between T cell kinetics in mice and men have fueled the idea that a young mouse is a good model system for a young human, and an old mouse, for an elderly human. By combining in vivo kinetic labeling using deuterated water, thymectomy experiments, analysis of T cell receptor excision circles and CD31 expression, and mathematical modeling, we have quantified the contribution of thymus output and peripheral naive T cell division to the maintenance of T cells in mice and men. Aging affected naive T cell maintenance fundamentally differently in mice and men. Whereas the naive T cell pool in mice was almost exclusively sustained by thymus output throughout their lifetime, the maintenance of the adult human naive T cell pool occurred almost exclusively through peripheral T cell division. These findings put constraints on the extrapolation of insights into T cell dynamics from mouse to man and vice versa.

In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2 H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term upand down-labeling with 2 H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool. recent thymic emigrants ͉ T cell half-lives ͉ T cell production T he role of the thymus in HIV infection is still poorly understood (1, 2). On the one hand, thymic failure has been suggested to play a crucial role in CD4 T cell loss during HIV infection (3), and rapid thymic rebound has been proposed to be responsible for T cell reconstitution during anti-viral treatment (4). However, it has been argued that thymic output in adults might be too low to have a large impact on CD4 T cell depletion (5). In general, these issues are addressed with estimates of thymic output, naïve and memory T cell production rates, and life spans that are simply extrapolated from observations in mice, monkeys, and lymphopenic or irradiated humans (6-11).Naïve T cells are generally thought to turnover relatively slowly, but it has been suggested that, in mice, a considerable part of the naïve T cell pool consists of RTEs with relatively rapid turnover (9, 10, 12). In humans, naïve T cell numbers, T cell receptor excision circles (TRECs), and expression of CD31 have been used to measure thymic output (7,13,14). Dion et al. (4) observed rapid changes in the Sj/V␤ TREC ratio within 3 months after infection with HIV, which suggested the presence of a rapidly turning over RTE pool in human adults containing most of the TRECs in the periphery, similar to young rodents and chickens (15, 16). However, because TRECs are long-lived, none of these approaches is specific for T cells that have recently emigrated from the thymus (1, 2, 5), and, therefore, they fail to quantify thymic output in humans.Peripheral T cell proliferation might also contribute to the maintenance of the naïve T cell pool in human adults; however, it is unclear which fraction of these cells remains in the naïve T cell pool (17). The contribution of RTEs and peripheral T cell proliferation to the maintenance of the naïve T cell pool can only be determined by studying the fate of newly produced T cells. In vivo labeling with stable isotopes in combination with appropriate mathematical analysis of these data provides a way to obtain T cell decay and production rates ...