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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation of late B cell differentiation by intrinsic IKKα-dependent signals
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Regulation of late B cell differentiation by intrinsic IKKα-dependent signals

机译：通过固有的IKKα依赖性信号调节晚期B细胞分化

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摘要

NF-κB-inducing kinase (NIK)-mediated IKKα phosphorylation activates the alternative NF-κB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-βR, BAFF-R, and CD40. Although NIK, IKKα, and p52 are all critical regulators of LT-βR signaling in stromal cells during humoral immune responses, lymphocytes require NIK, but not p52, for optimal Ig production. This disparity suggests that NIK possesses critical cell-type-specific functions that do not depend on NF-κB. Here we use mice bearing targeted mutations of the IKKα activation loop Ser~(176/180) (IKKα~(AA)) to address the B cell-intrinsic functions of NIK-IKKα signaling in vivo. We find that IKKα~(AA) B cells mount normal primary antibody responses but do not enter germinal centers. This defect likely derives from ineffective early T-B cell collaboration and leads to impaired generation of humoral memory and relatively short-lived, low-affinity antibody production. Our findings contrast with those obtained by using p52~(-/-) B cells, which mount normal Ig responses, and alym-phoplasia (NIK mutant) B cells, which produce very little primary Ig. Thus, the NIK-IKKα-p52 axis is not as linear and exclusive as previous studies suggest, and IKKα possesses critical NF-κB-independent functions in B cells.
机译：NF-κB诱导激酶（NIK）介导的IKKα磷酸化激活了替代性NF-κB途径，其特征是p52：RelB异二聚体的核易位。此替代途径由少数几种受体（包括LT-βR，BAFF-R和CD40）启动。尽管在体液免疫反应期间，NIK，IKKα和p52都是基质细胞中LT-βR信号传导的关键调节因子，但淋巴细胞需要NIK而非p52才能获得最佳的Ig产生。这种差异表明NIK具有不依赖于NF-κB的关键细胞类型特异性功能。在这里，我们使用带有IKKα激活环Ser〜（176/180）（IKKα〜（AA））靶向突变的小鼠来研究NIK-IKKα信号传导的B细胞内在功能。我们发现IKKα〜（AA）B细胞安装正常的一抗反应，但不进入生发中心。该缺陷可能源于无效的早期T-B细胞协作，并导致体液记忆的产生受损和相对短暂的低亲和力抗体产生。我们的发现与使用正常Ig反应的p52〜（-/-）B细胞和产生极少原发Ig的无性腺增生（NIK突变）B细胞所获得的结果相反。因此，NIK-IKKα-p52轴不像以前的研究那样线性且排他，IKKα在B细胞中具有关键的NF-κB独立功能。

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