Dock8 regulates BCR signaling and activation of memory B cells via WASP and CD19
Dock8 regulates BCR signaling and activation of memory B cells via WASP and CD19
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Dock8 通过 WASP 和 CD19 调节 BCR 信号传导和记忆 B 细胞的激活。
DOI：
10.1182/bloodadvances.2017007880
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发表时间：
2018-02-27
期刊：
影响因子：
7.5
通讯作者：
Liu, Chaohong
中科院分区：
文献类型：
--
作者：
Sun, Xiaoyu;Wang, Jinzhi;Liu, Chaohong
Dock 8缺陷导致免疫缺陷，并且Dock 8在B细胞发育和功能中的作用已经被揭示;然而，Dock 8对B细胞受体（BCR）信号传导和记忆B细胞功能的作用仍然难以捉摸。本研究通过建立Dock 8基因敲除小鼠模型，收集Dock 8患者外周血单个核细胞，采用共聚焦显微镜和全内反射荧光显微镜研究Dock 8基因敲除对BCR信号转导和记忆B细胞活化的影响。关键的正上游BCR信号分子pCD 19和磷酸化Brutons酪氨酸激酶（pBtk）的激活减少。有趣的是，Wiskott-Aldrich综合征蛋白（WASP）的总蛋白和活化水平在Dock 8缺陷型小鼠B细胞中降低。我们前期的研究表明WASP对cd 19的转录有正调控作用，而且我们发现Dock 8对cd 19的转录有调控作用。我们在Dock 8患者中发现的可能是从Dock 8小鼠复制的表型。来自Dock 8患者的记忆B细胞的早期激活被破坏，BCR聚集减少，B细胞扩散和信号体募集到幼稚B细胞的程度，以及从幼稚B细胞向未转换的记忆B细胞的转变。总的来说，我们的研究提供了一种新的机制，Dock 8通过调节cd 19转录调节BCR信号，以及Dock 8患者记忆B细胞非能力的潜在机制。
Dock8 deficiency leads to immunodeficiency, and the role of Dock8 in B-cell development and function has been revealed; however, the role of DocK8 on B-cell receptor (BCR) signaling and function of memory B cells remains elusive. In this study, we generated a Dock8 knockout mouse model and collected peripheral blood mononuclear cells from Dock8 patients to study the effect of Dock8 deficiency on the BCR signaling and activation of memory B cells with confocal microscopy and total internal reflection fluorescence microscopy. The activation of key, positive upstream BCR signaling molecules, pCD19 and phosphorylated Brutons tyrosine kinase (pBtk), is reduced. Interestingly, the total protein and activated levels of Wiskott-Aldrich syndrome protein (WASP) are decreased in Dock8-deficient mouse B cells. Our previous research has shown that WASP positively regulates cd19 transcription; furthermore, we found that Dock8 regulates cd19 transcription. What we found in Dock8 patients can be a phenotype copied from Dock8 mice. The early activation of memory B cells from Dock8 patients is disrupted with reduced BCR clustering, B-cell spreading, and signalosome recruitment into the degree of naïve B cells, as well as the transition from naïve B cells to unswitched memory B cells. Overall, our study provides a novel mechanism for Dock8 regulation of BCR signaling by regulating cd19 transcription, as well as the underlying mechanism of noncompetence of memory B cells in Dock8 patients.