Control of Toll-like receptor-mediated T cell-independent type 1 antibody responses by the inducible nuclear protein IκB-ζ.
Control of Toll-like receptor-mediated T cell-independent type 1 antibody responses by the inducible nuclear protein IκB-ζ.
复制标题
通过诱导型核蛋白IκB-ζ对TOLL样受体介导的T细胞介导的T细胞1抗体反应的控制。
DOI：
10.1074/jbc.m114.553230
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发表时间：
2014-11-07
期刊：
影响因子：
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通讯作者：
MaruYama T
中科院分区：
文献类型：
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作者：
Hanihara-Tatsuzawa F;Miura H;Kobayashi S;Isagawa T;Okuma A;Manabe I;MaruYama T
背景：IκB-κ B是核蛋白IκB家族的一员，可被Toll样受体（TLR）信号诱导。结果：IκB-κ B缺陷可降低B细胞的T细胞非依赖性抗体反应-1。结论：IκB-κ B是B细胞中TLR介导的类转换重组（CSR）的关键调节因子。意义：T细胞依赖性和非依赖性抗体应答受不同机制调节。抗体应答已被分类为T细胞依赖性或T细胞非依赖性（TI）。TI抗体应答根据其对B细胞介导的抗原受体信号传导的需要进一步分类为1型（TI-1）或2型（TI-2）。尽管抗体应答的机制基础已被广泛研究，但仍不清楚不同的抗体应答是否在其转录调控中具有相似性。在这里，我们表明，小鼠缺乏IκB-κ B，特别是在他们的B细胞，有受损的TI-1抗体反应，但正常的T细胞依赖性和TI-2抗体反应。B细胞中IκB-κ B的缺乏也损害了由Toll样受体（TLR）激活、浆细胞分化和类别转换重组（CSR）触发的增殖。从机制上讲，IκB-β缺陷型B细胞不能诱导TLR介导的激活诱导型胞苷脱氨酶（AID）（一种类别转换DNA重组酶）的诱导。在IκB-β-D缺陷型B细胞中，AID的逆转录病毒转导恢复了CSR活性。此外，相对于IκB-β表达的B细胞，Iκ B-β缺陷的B细胞中编码AID的基因的转录起始位点附近的组蛋白H3的乙酰化减少。这些结果表明IκB-κ B通过诱导AID调节TLR介导的CSR。此外，IκB-κ B定义了不同抗体应答的转录调节差异。
Background: IκB-ζ, a member of the IκB family of nuclear proteins that regulates transcription, can be induced by Toll-like receptor (TLR) signaling. Results: IκB-ζ deficiency in B cells reduced T cell-independent antibody response-1. Conclusion: IκB-ζ is a key regulator of TLR-mediated class switch recombination (CSR) in B cells. Significance: T cell-dependent and -independent antibody responses are regulated by different mechanisms. Antibody responses have been classified as being either T cell-dependent or T cell-independent (TI). TI antibody responses are further classified as being either type 1 (TI-1) or type 2 (TI-2), depending on their requirement for B cell-mediated antigen receptor signaling. Although the mechanistic basis of antibody responses has been studied extensively, it remains unclear whether different antibody responses share similarities in their transcriptional regulation. Here, we show that mice deficient in IκB-ζ, specifically in their B cells, have impaired TI-1 antibody responses but normal T cell-dependent and TI-2 antibody responses. The absence of IκB-ζ in B cells also impaired proliferation triggered by Toll-like receptor (TLR) activation, plasma cell differentiation, and class switch recombination (CSR). Mechanistically, IκB-ζ-deficient B cells could not induce TLR-mediated induction of activation-induced cytidine deaminase (AID), a class-switch DNA recombinase. Retroviral transduction of AID in IκB-ζ-deficient B cells restored CSR activity. Furthermore, acetylation of histone H3 in the vicinity of the transcription start site of the gene that encodes AID was reduced in IκB-ζ-deficient B cells relative to IκB-ζ-expressing B cells. These results indicate that IκB-ζ regulates TLR-mediated CSR by inducing AID. Moreover, IκB-ζ defines differences in the transcriptional regulation of different antibody responses.