Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice
Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice
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DOI：
10.4049/jimmunol.168.6.2695
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发表时间：
2002-03-15
影响因子：
4.4
通讯作者：
Hendriks, RW
中科院分区：
文献类型：
--
作者：
Middendorp, S;Dingjan, GM;Hendriks, RW
Bruton‘s酪氨酸激酶(BTK)是一种细胞质信号分子，对人类前体细胞(Pre-B)的分化至关重要。在这项研究中，我们发现在小鼠从大周期到小静息前B细胞的转变过程中，BTK基因缺陷的细胞不能有效地调节CD43、代理L链、CD2和CD25的表达。在对体内前B细胞分化动力学的分析中，与野生型细胞相比，BTK缺陷细胞在小的前B细胞间隔内表现出一种特殊的发育延迟，与野生型细胞相似，延迟了3小时。同样，在体外骨髓培养中，BTK缺陷的大周期Pre-13细胞表现出IL-7介导的增殖增加，并减缓了发育进程，使其成为非周期CD2(+)CD25(+)替代链阴性的小Pre-13细胞，随后发展为Ig阳性的B细胞。此外，BTK的缺失导致重组激活基因-1缺陷的Pro-B细胞对IL-7的增殖反应增强。这些发现确定了BTK在调节前-B和前-B细胞中IL-7反应的分化阶段特异性调节中的新作用。此外，我们的结果表明，BTK对于有效地穿过小的Pre-B细胞室，从而在表达Pre-B细胞的细胞质g H链向未成熟的IgM(+)B细胞的发育过程中调节细胞表面表型的变化至关重要。
Bruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is crucial for precursor (pre-B) cell differentiation in humans. In this study, we show that during the transition of large cycling to small resting pre-B cells in the mouse, Btk-deficient cells failed to efficiently modulate the expression of CD43, surrogate L chain, CD2, and CD25. In an analysis of the kinetics of pre-B cell differentiation in vivo, Btk-deficient cells manifested a specific developmental delay within the small pre-B cell compartment of similar to3 h, when compared with wild-type cells. Likewise, in in vitro bone marrow cultures, Btk-deficient large cycling pre-13 cells showed increased IL-7 mediated expansion and reduced developmental progression into noncycling CD2(+)CD25(+) surrogate L chain-negative small pre-13 cells and subsequently into Ig-positive B cells. Furthermore, the absence of Btk resulted in increased proliferative responses to IL-7 in recombination-activating gene-1-deficient pro-B cells. These findings identify a novel role for Btk in the regulation of the differentiation stage-specific modulation of IL-7 responsiveness in pro-B and pre-B cells. Moreover, our results show that Btk is critical for an efficient transit through the small pre-B cell compartment, thereby regulating cell surface phenotype changes during the developmental progression of cytoplasmic g H chain expressing pre-B cells into immature IgM(+) B cells.