Conserved and divergent aspects of human T-cell development and migration in humanized mice.
Conserved and divergent aspects of human T-cell development and migration in humanized mice.
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DOI：
10.1038/icb.2015.38
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发表时间：
2015-09
影响因子：
4
通讯作者：
Melichar HJ
中科院分区：
文献类型：
--
作者：
Halkias J;Yen B;Taylor KT;Reinhartz O;Winoto A;Robey EA;Melichar HJ
人源化小鼠是研究人类免疫系统发育和功能的重要模型。虽然已知小鼠胸腺基质细胞可以支持人类 T 细胞发育，但种间串扰的程度以及这些系统在多大程度上重现正常人类 T 细胞发育仍不清楚。为了解决这些问题，我们将新生嵌合体人源化小鼠模型中的常规和非常规 T 细胞发育与人类胎儿和新生儿胸腺样本中的发育进行了比较，并检查了小鼠基质表达的人类 HLA-A2 转基因的影响。鉴于动态迁移和细胞间相互作用对于 T 细胞分化至关重要，我们还研究了在小鼠胸腺环境中发育的人类胸腺细胞的胸腺内迁移模式。我们发现人源化小鼠的传统 T 细胞发育和胸腺内迁移模式与人类胸腺生成非常相似。此外，我们还发现，发育中的人类胸腺细胞与其他人类造血细胞发生短暂、连续的相互作用。然而，人源化小鼠的非常规 T 细胞分化不同于胎儿和新生儿的人类胸腺生成，包括 Foxp3+ T 细胞发育的明显缺陷。这些数据表明，尽管小鼠胸腺微环境可以支持人类 T 细胞发育的许多方面，但仍然存在重要差异，并且可能需要额外的人类特异性因素。
Humanized mice represent an important model to study the development and function of the human immune system. While it is known that mouse thymic stromal cells can support human T-cell development, the extent of interspecies cross-talk and the degree to which these systems recapitulate normal human T-cell development remain unclear. To address these questions, we compared conventional and non-conventional T-cell development in a neonatal chimera humanized mouse model with that seen in human fetal and neonatal thymus samples, and also examined the impact of a human HLA-A2 transgene expressed by the mouse stroma. Given that dynamic migration and cell–cell interactions are essential for T-cell differentiation, we also studied the intrathymic migration pattern of human thymocytes developing in a murine thymic environment. We found that both conventional T-cell development and intra-thymic migration patterns in humanized mice closely resemble human thymopoiesis. Additionally, we show that developing human thymocytes engage in short, serial interactions with other human hematopoietic-derived cells. However, non-conventional T-cell differentiation in humanized mice differed from both fetal and neonatal human thymopoiesis, including a marked deficiency of Foxp3+ T-cell development. These data suggest that although the murine thymic microenvironment can support a number of aspects of human T-cell development, important differences remain, and additional human-specific factors may be required.