Human αβ and γδ thymocyte development:: TCR gene rearrangements, intracellular TCRβ expression, and γδ developmental potential-differences between men and mice
Human αβ and γδ thymocyte development:: TCR gene rearrangements, intracellular TCRβ expression, and γδ developmental potential-differences between men and mice
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DOI：
10.4049/jimmunol.176.3.1543
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Thompson, LF
中科院分区：
文献类型：
--
作者：
Joachims, ML;Chain, JL;Thompson, LF
为了评估TCR在人类胸腺细胞发育过程中α β / γ δ谱系选择中的作用，对γ δ细胞中的TCR位点以及α β细胞中的TCR β和S位点进行了分子分析。在gamma delta细胞中，TCRP可变基因片段在很大程度上保留在种系结构中，这表明在大多数情况下，对gamma delta谱系的承诺发生在TCR β完全重排之前。检测到的少数TCRP重排主要是框架外的，这表明多产的TCRP重排使细胞远离了γ δ谱系。相反，在α - β细胞中，TCR γ位点几乎完全重排，具有随机的生产力特征；TCR δ基因座主要包含非生产性重排。然而，与预先选择的细胞相比，生产性γ重排被耗尽。产生TCR γ和5重排很少发生在同一细胞中，这表明α - β细胞是从不能产生功能性γ δ TCR的细胞发育而来的。细胞内TCRP的表达与CD4的上调和CD34的下调相关，并在双阳性早期趋于稳定。然而，令人惊讶的是，一些早期双阳性胸腺细胞在培养中保留了伽马δ电位。我们提出了一个人类胸腺发育模型，其中包括伽马δ发育作为默认途径，TCR在α β / γ δ谱系选择中的指导作用，以及β选择和γ δ谱系承诺的延长发育窗口。与小鼠不同的方面是TCR基因在非表达位点重排的状态，A选择的时间，以及在早期双阳性发育阶段维持γ δ电位。
To evaluate the role of the TCR in the alpha beta/gamma delta lineage choice during human thymocyte development, molecular analyses of the TCR locus in gamma delta cells and the TCR beta and S loci in alpha beta cells were undertaken. TCRP variable gene segments remained largely in germline configuration in gamma delta cells, indicating that commitment to the gamma delta lineage occurred before complete TCR beta rearrangements in most cases. The few TCRP rearrangements detected were primarily out-of-frame, suggesting that productive TCRP rearrangements diverted cells away from the gamma delta lineage. In contrast, in alpha beta cells, the TCR gamma locus was almost completely rearranged with a random productivity profile; the TCR delta locus contained primarily nonproductive rearrangements. Productive gamma rearrangements were, however, depleted compared with preselected cells. Productive TCR gamma and 5 rearrangements rarely occurred in the same cell, suggesting that alpha beta cells developed from cells unable to produce a functional gamma delta TCR. Intracellular TCRP expression correlated with the up-regulation of CD4 and concomitant down-regulation of CD34, and plateaued at the early double positive stage. Surprisingly, however, some early double positive thymocytes retained gamma delta potential in culture. We present a model for human thymopoiesis which includes gamma delta development as a default pathway, an instructional role for the TCR in the alpha beta/gamma delta lineage choice, and a prolonged developmental window for beta selection and gamma delta lineage commitment. Aspects that differ from the mouse are the status of TCR gene rearrangements at the nonexpressed loci, the timing of A selection, and maintenance of gamma delta potential through the early double positive stage of development.