Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice
Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice
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DOI：
10.1073/pnas.1517246112
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发表时间：
2015-12-15
影响因子：
11.1
通讯作者：
Seddon, Benedict
中科院分区：
文献类型：
--
作者：
Hogan, Thea;Gossel, Graeme;Seddon, Benedict
了解我们的 T 细胞区室如何维持需要了解其群体动态，通常使用纳入分裂细胞 DNA 的标签管理在数天到数周内进行量化。这些研究提供了稳态动力学的快照，并表明淋巴细胞群在分裂和/或死亡率方面是异质的，尽管解决这种异质性的细节是有问题的。在这里，我们提出了一种研究小鼠 T 细胞在数月至数年时间尺度上的群体动态的方法，该方法揭示了分裂率和死亡率相对于胸腺输出时宿主年龄的异质性。我们使用移植调理药物白消安来消除幼鼠的造血干细胞，但保持外周淋巴细胞区室完好无损。用同源标记（供体）骨髓重建后，我们在治疗后一年内跟踪用供体来源的淋巴细胞稀释外周宿主 T 细胞。用数学模型描述这些动力学，我们估计了初始 CD4 和 CD8 T 细胞的胸腺产生、分裂和死亡的速率。对平均寿命的群体平均估计与早期的研究一致，但我们发现最有力的支持模型是，两个初始 T 细胞库都包含动力学上不同的较旧宿主衍生细胞亚群，这些细胞具有自我更新能力，能够抵抗初始供体淋巴细胞的置换。我们推测这些现有细胞通过稳态扩张进入淋巴细胞减少的新生儿环境来调节或选择以增强适应性
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