A T cell controlled molecular pathway regulating the IgH locus: CD40-mediated activation of the IgH 3' enhancer
A T cell controlled molecular pathway regulating the IgH locus: CD40-mediated activation of the IgH 3' enhancer
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DOI：
10.1002/j.1460-2075.1996.tb01059.x
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发表时间：
1996-12-02
期刊：
影响因子：
11.4
通讯作者：
Pettersson, S
中科院分区：
文献类型：
--
作者：
Grant, PA;Andersson, T;Pettersson, S
免疫球蛋白重链（IgH）类别转换重组和IgH表达水平的调节被认为是由IgH 3'增强子控制的过程。在此，我们证明了原代B细胞的CD 40或IgM受体刺激导致该增强子的反式激活，4-羟基-3-硝基苯乙酰基（NIP）-BSA诱导表达嵌合NIP特异性CD 40单链受体的K46 B细胞系产生配体受体-3 ′增强子ETS/AP-1最小启动子构建体依赖性应答、凝胶阻滞分析和基因组足迹实验揭示了CD 40或IgM诱导募集NFAB虽然IgM信号传导募集c-Fos、JunB和Elf-1（NFAB-I），但在CD 40信号传导后仅观察到JunB和Elf-1（NFAB-II），然而，CD 40信号转导诱导JunB的Fos家族相关伴侣，这可能解释了在K46细胞中通过NFAB-II观察到的转录活性。我们提出了一个模型，其中CD 40和IgM受体介导的信号转导在B淋巴细胞3'增强子激活过程中会聚。我们的数据提供了一个假定的分子解释，为什么CD 40 L缺陷的小鼠，并可能与高IgM综合征患者，不能进行T细胞依赖的类转换重组，但适当的响应后脂多糖诱导的开关重组。
Immunoglobulin heavy chain (IgH) class switch recombination and regulation of IgH expression levels are processes suggested to be controlled by the IgH 3' enhancer, Here we demonstrate that CD40 or IgM receptor stimulation of primary B cells results in transactivation of this enhancer, 4-Hydroxy-3-nitrophenylacetyl (NIP)-BSA induction of a K46 B cell line expressing a chimeric NIP-specific CD40 single chain receptor results in a ligand receptor-dependent response of a 3' enhancer ETS/AP-1 minimal promoter construct, Gel retardation analysis and genomic footprinting experiments reveal that CD40 or IgM induction recruits NFAB (nuclear factors of activated B cells) to the ETS/AP-1 motif, While IgM signalling recruits c-Fos, JunB and Elf-1 (NFAB-I), only JunB and Elf-1 were observed following CD40 signalling (NFAB-II), CD40 signalling, however, induces a Fos family-related partner for JunB, which may account for the transcriptional activity observed by NFAB-II in K46 cells, We propose a model whereby CD40 and IgM receptor-mediated signalling converge in the process of 3' enhancer activation in B lymphocytes. Our data provide a putative molecular explanation as to why CD40L-deficient mice, and possibly patients with hyper-IgM syndrome, are unable to undergo T cell-dependent class switch recombination but respond properly upon lipopolysaccharide-induced switch recombination.