Productive T-cell receptor beta-chain gene rearrangement: Coincident regulation of cell cycle and clonality during development in vivo
Productive T-cell receptor beta-chain gene rearrangement: Coincident regulation of cell cycle and clonality during development in vivo
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DOI：
10.1101/gad.10.8.948
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发表时间：
1996-04-15
影响因子：
10.5
通讯作者：
Hayday, AC
中科院分区：
文献类型：
--
作者：
Hoffman, ES;Passoni, L;Hayday, AC
T细胞受体(TCR) β链位点的多产基因重排促进了“前TCR”的形成，这是一种分子复合物，对α - β T细胞的后续发育很重要。胸腺细胞从具有TCR - β链基因的细胞群向具有TCR - β链基因有效重排的细胞群的转变被称为“β选择”。“这是α - β t细胞发育的第一个点，在这个点上，激活的TCR位点的产物定义了细胞表型。为了理解这些事件，本研究集中在一组由细胞表面表型定义为HSA(+) CD44（低）CD25（+）的胸腺细胞上，其中大部分TCR β基因重排发生。对这个集合的分析，在这里，允许将其新细分为两个子集，分别是紧跟在TCR β选择之前和之后的强大候选细胞。通过β选择的细胞与之前的细胞有几个不同的标准，包括Rb的过度磷酸化，细胞周期蛋白A和B的表达增加，p27的下调，CDK2活性增加，cdc2活性的诱导，以及通过DNA合成的进展。与这些可归因于高产TCR β链基因重排的变化相一致，在不能组装前TCR的突变小鼠中未检测到确定的“β选择”亚群。有趣的是，RAG2蛋白的选择性和短暂性下调是一致的，TCR基因重排依赖于RAG2蛋白的选择性和短暂性下调。总之，这些发现表明，TCR基因重排与确保胸腺细胞扩增和单克隆的事件有关。
Productive gene rearrangement at the T-cell receptor (TCR) beta-chain locus facilitates formation of the ''pre-TCR,'' a molecular complex that is important for the subsequent development of alpha beta T cells. The transition of thymocytes from a population of cells undergoing TCR beta chain genes to a population enriched in cells with productively rearranged TCR beta chain genes is known as ''beta selection.'' This is the first point in alpha beta T-cell development at which the products of an activated TCR locus define cell phenotype. Toward an understanding of these events, this study has focused on a set of thymocytes defined by cell surface phenotype as HSA(+) CD44(low) CD25(+), in which the bulk of TCR beta gene rearrangement occurs. The analysis of this set, presented here, allows its novel subdivision into two subsets that are respectively strong candidates for cells immediately prior to and immediately following TCR beta selection. Cells that have passed beta selection differ from the preceding cells by several criteria, including hyperphosphorylation of Rb, increased expression of cyclins A and B, down-regulation of p27, increased CDK2 activity, an induction of cdc2 activity, and progression through DNA synthesis. Consistent with these changes being attributable to productive TCR beta chain gene rearrangement, the identified ''beta-selected'' subset is not detected in mutant mice that cannot assemble a pre-TCR. Interestingly, there is a coincident selective and transient down-regulation of the protein RAG2, on which TCR gene rearrangement obligatorily depends. Together, these findings demonstrate that productive TCR gene rearrangement is associated with events that can ensure thymocyte expansion and monoclonality.