Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling
Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling
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DOI：
10.1016/j.immuni.2007.12.019
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发表时间：
2008-03-01
期刊：
影响因子：
32.4
通讯作者：
Singh, Harinder
中科院分区：
文献类型：
--
作者：
Johnson, Kristen;Hashimshony, Tamar;Singh, Harinder
免疫球蛋白重链基因座的生产性重排触发主要发育检查点，其促进前B细胞的有限克隆扩增，从而最终导致细胞周期停滞和轻链基因座的重排。通过使用Irf 4（-/-）Irf 8（-/-）前B细胞，我们证明了两种途径会聚以协同驱动轻链重排，而不仅仅是细胞周期退出的结果。一种途径直接依赖于转录因子IRF-4，其表达通过前B细胞受体信号传导而升高。IRF-4靶向免疫球蛋白3 ' E κ和E λ增强子，并将κ等位基因定位在远离着丝粒周围异染色质的位置。另一个途径是通过减弱IL-7信号传导触发的，并通过转录因子E2 A的结合激活iE κ增强子。IRF-4还调节趋化因子受体Cxcr 4的表达，并促进前B细胞响应趋化因子配体CXCL 12的迁移。我们认为IRF-4通过将前B细胞定位在远离表达IL-7的基质细胞的位置来协调调节轻链重组的两种途径。
Productive rearrangement of the immunoglobulin heavy-chain locus triggers a major developmental checkpoint that promotes limited clonal expansion of pre-B cells, thereby culminating in cell-cycle arrest and rearrangement of light-chain loci. By using Irf4(-/-) Irf8(-/-) pre-B cells, we demonstrated that two pathways converge to synergistically drive light-chain rearrangement, but not simply as a consequence of cell-cycle exit. One pathway was directly dependent on transcription factor IRF-4, whose expression was elevated by pre-B cell receptor signaling. IRF-4 targeted the immunoglobulin 3 ' E kappa and E lambda enhancers and positioned a kappa allele away from pericentromeric heterochromatin. The other pathway was triggered by attenuation of IL-7 signaling and activated the iE kappa enhancer via binding of the transcription factor E2A. IRF-4 also regulated expression of chemokine receptor Cxcr4 and promoted migration of pre-B cells in response to the chemokine ligand CXCL12. We propose that IRF-4 coordinates the two pathways regulating light-chain recombination by positioning pre-B cells away from IL-7-expressing stromal cells.