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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- "However, the ratio between sjTRECs (generated after many rounds of intrathymic proliferation) and βTRECs (generated early in thymocyte maturation) indicates the extent of intrathymic proliferation , which determines the thymic output of naïve T cells . In previous studies, this analysis of ratios has confirmed that sjTREC levels provide a good indication of thymic output, and are not hugely influenced by peripheral proliferation , . Nevertheless the reliability of measuring sjTRECs to infer thymic output has not yet been unanimously accepted. "
ABSTRACT: HIV-1(+) individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4(+) T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression. CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-gamma ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1(+) individuals originally identified as "Long-term non-progressors" in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-gamma producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-gamma production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1(+) patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-gamma production and proliferative T-cell function also declines in 2 HIV controllers over 22 years. Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory.PLoS ONE 02/2009; 4(5):e5474. DOI:10.1371/journal.pone.0005474 · 3.23 Impact Factor
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.