Thymic output and HIV infection: on the right TREC.
ABSTRACT The role of the thymus in HIV infection has been a matter of considerable debate. A new study by Dion et al. (2004) in this issue of Immunity provides the mechanism for reduced thymic output in HIV infection while illuminating the impact of recent thymic emigrants on peripheral T cell homeostasis.
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Article: Leukocyte dynamics in mice and men[Show abstract] [Hide abstract]
ABSTRACT: Our limited knowledge of the expected life spans of granulocytes and T cells during health and disease hampers our understanding of the functioning of the immune system. Using stable isotope labeling we estimated the average life spans of human circulating granulocytes to be 6 days. This estimate was 10-fold higher than suggested in previous reports, supporting the emerging concept that neutrophils participate in complex long-term processes, such as immune regulation and recirculation. Since life span estimates of kinetically heterogeneous cell populations is labeling-time dependent, a new modeling strategy was introduced to fit average life spans independent of the labeling period. Deuterium labeling in human adults revealed a low daily production of naive T cells. Whereas naive T cells lived on average 6.0 (naive CD4+) and 9.4 years (naive CD8+), the few naive T cells that were recently produced had an even longer life expectancy. These data are incompatible with the existence of a substantial short-lived population of recent thymic emigrants in human adults. In contrast, a considerable thymic output was observed in mice. In addition, thymic emigrants lived as long as the average murine naive T cell in the periphery (48 and 83 days for naive CD4+ and CD8+ T cells, respectively), suggesting that the murine naive T-cell pool is kinetically homogeneous, which is incompatible with the co-existence of short-lived thymic emigrants and long-lived truly naive T cells. The different life expectancy of recently produced naive T cells in adult mice and men suggests different homeostatic mechanisms of naive T cells in the two species. Indeed, thymectomy experiments and TREC analyses in ageing mice revealed that almost all murine naive T cells represent thymic emigrants, whereas TREC analysis in ageing humans strongly suggests that the majority of newly produced human naive T cells is derived from peripheral proliferation. Since the mechanism of naive T-cell maintenance is fundamentally different in mice and men, this will influence the diversity of the TCR repertoire of the species. The difference in naive T-cell dynamics suggests that laboratory mice, which are worldwide used as a model to study T-cell dynamics in men, are not a good model to study naive T-cell homeostasis in humans. Chronic immune activation in HIV-1 infection plays an important role in CD4+ T-cell depletion. Using CD70Tg mice, we showed that even in the context of substantial thymic output, like in young children, chronic immune activation can lead to severe naive T-cell depletion. In human adults with a much lower thymic output, even moderately enhanced priming rates may lead to severe T-cell depletion. Collectively, these data shed a new light on the dynamics of granulocytes and T cells and point to a serious limitation regarding extrapolation of insights from mouse to man and vice versa.
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ABSTRACT: A key determinant of T cell dynamics in HIV-1 infection is the status of thymic function. To date, most studies of the impact of HIV-1 on the thymus during early HIV-1 infection have been done in samples collected in the interval of 3-12 months after infection. In this study, we have probed the status of thymic function and peripheral naive T cells in patients with acute HIV-1 infection diagnosed 18-72 days after the onset of symptoms. We found that peripheral CD4 and CD8 T cell proliferation was initially elevated, then waned over time. The fall in T cell proliferation correlated with a reduction in HIV-1 viral RNA levels and a rise in peripheral blood CD4+ CD25+ T cells. In spite of elevated T cell proliferation early on in primary HIV-1 infection, levels of naive phenotype CD4 and CD8 T cells and T cell receptor excision circle positive cells (sjTREC(+)) remained constant. Taken together with the observation that T cell proliferation normally dilutes peripheral T cell episomal sjTREC levels, these data suggested that thymopoiesis contributes to maintenance of the naive T cell pool during the earliest stages of HIV-1 infection (18-72 days).Journal of Clinical Immunology 10/2005; 25(5):462-72. DOI:10.1007/s10875-005-5635-4 · 2.65 Impact Factor