Thymic output in aged mice

Hale, J. Scott; Boursalian, Tamar E.; Turk, Gail L.; Fink, Pamela J.

doi:10.1073/pnas.0601040103

Cited by 276 publications

(325 citation statements)

References 36 publications

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“…The total number of naive T cells is ϳ10 11 cells (30), which declines marginally in 80 years and is in the model almost entirely composed of truly naive T cells because the RTEs form a much smaller subpopulation (Fig. 3a) (29). The RTE pool decreases proportionally to the thymic output, which decreases Ͼ100-fold and is close to the previously estimated 10 8 cells d Ϫ1 at age 30 (30).…”

Section: Model Behaviormentioning

confidence: 56%

The Effects of Age, Thymectomy, and HIV Infection on α and β TCR Excision Circles in Naive T Cells

Dool

Boer

2006

The Journal of Immunology

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Due to homeostasis total naive T cell numbers remain fairly constant over life despite a gradual involution of the thymus. The contribution of the thymus to maintaining naive T cell pools is typically measured with TCR excision circles (TRECs) that are formed in thymocytes. The mechanisms underlying thymic involution are poorly understood. Some data suggest that thymocytes undergo fewer divisions in old (small) than young (large) thymi, and other data suggest that the number of TRECs per thymocyte is independent of age. If thymic involution were associated with a decreased number of divisions of the thymocytes, this would markedly complicate the interpretation of TREC data. To study this we develop a mathematical model in which the division rate of thymocytes decreases with increasing age. We describe the dilution of TRECs formed during the arrangement of both chains of the TCR by division of thymocytes, recent thymic emigrants, and mature naive T cells. The model behavior is complicated as TREC contents in naive T cells can increase with age due to decreased dilution in the thymus. Because our model is consistent with current data on the effects of age and thymectomy on TRECs in peripheral T cells, we conclude that aging may well affect thymocyte division, which markedly complicates the interpretation of TREC data. It is possible, but more difficult, to let the model be consistent with the rapid changes in α and β TRECs observed shortly after HIV infection.

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Section: Model Behaviormentioning

confidence: 56%

The Effects of Age, Thymectomy, and HIV Infection on α and β TCR Excision Circles in Naive T Cells

Dool

Boer

2006

The Journal of Immunology

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“…Uncertainty in the second and third columns stems largely from uncertainty in the division rate, ρ. and 8.8 for CD4 and CD8, respectively (fits shown in SI Appendix S9). Further, declining rates of RTE maturation are at odds with the observation that the frequency of RTE scales with the size of the thymus (34). It has also been inferred from a small dataset that RTE in humans may themselves be kinetically heterogeneous and include a subset of exceptionally long-lived veteran cells that retain immature status (35).…”

Section: Discussionmentioning

confidence: 67%

Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice

Hogan

Gossel

Yates

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment.T-cell homeostasis | mathematical modeling | Ki67 | kinetic heterogeneity N ormal adaptive immunity depends on maintaining populations of naive CD4 and CD8 T cells of sufficient sizes and diversities of antigen receptors. Mature naive cells are generated by the thymus and, once in the periphery, divide slowly and are lost either to death or differentiation into effector cells. It is known qualitatively how both cytokine (1-7) and T-cell receptor (TCR) (4, 8, 9) signals influence their survival and self-renewal through division, but we still lack a quantitative understanding of the rules that govern the development and persistence of our naive T-cell repertoires.To develop our understanding of lymphocyte homeostasis, much effort has been directed at defining the kinetics of T cells under normal physiological conditions. Division and death are normally quantified by following the accumulation and loss of cells labeled in vivo with BrdU or deuterium from heavy water or deuterated glucose, taken up by dividing cells during administration of label and diluted following its withdrawal (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). These experiments are typically performed over days to weeks and collectively have revealed that cell populations initially assumed to be homogenous may in fact comprise multiple subpopulations dividing and dying at different rates (kinetic ...

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“…Recirculation of peripheral mature T cells back to the neonatal thymus (46) and of activated cells to the adult thymus (47) was shown some time ago. Very recently, recirculation of naive peripheral T cells back to the aging thymus has been demonstrated (48). In the pT␣ Ϫ/Ϫ thymus, CD4 SP were enriched in memory-like cells.…”

Section: Discussionmentioning

confidence: 99%

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Bosco

Agenès

Rolink

et al. 2006

The Journal of Immunology

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In pre-Tα (pTα) gene-deleted mice, the positively selectable CD4+CD8+ double-positive thymocyte pool is only 1% that in wild-type mice. Consequently, their peripheral T cell compartment is severely lymphopenic with a concomitant increase in proportion of CD25+FoxP3+ regulatory T cells. Using mixed bone marrow chimeras, where thymic output was 1% normal, the pTα−/− peripheral T cell phenotype could be reproduced with normal cells. In the pTα−/− thymus and peripheral lymphoid organs, FoxP3+CD4+ cells were enriched. Parabiosis experiments showed that many pTα−/−CD4+ single-positive thymocytes represented recirculating peripheral T cells. Therefore, the enrichment of FoxP3+CD4+ single-positive thymocytes was not solely due to increased thymic production. Thus, the pTα−/− mouse serves as a model system with which to study the consequences of chronic decreased thymic T cell production on the physiology of the peripheral T cell compartment.

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Thymic output in aged mice

Cited by 276 publications

References 36 publications

The Effects of Age, Thymectomy, and HIV Infection on α and β TCR Excision Circles in Naive T Cells

The Effects of Age, Thymectomy, and HIV Infection on α and β TCR Excision Circles in Naive T Cells

Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

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