Pathak Simanta, Ma Shibin, Trinh Long, Lu Runqing
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Mol Cell Biol. 2008 Apr;28(8):2815-24. doi: 10.1128/MCB.01946-07. Epub 2008 Feb 19.
Receptor editing is the primary means through which B cells revise antigen receptors and maintain central tolerance. Previous studies have demonstrated that interferon regulatory factor 4 (IRF-4) and IRF-8 promote immunoglobulin light-chain rearrangement and transcription at the pre-B stage. Here, the roles of IRF-4 and -8 in receptor editing were analyzed. Our results show that secondary rearrangement was impaired in IRF-4 but not IRF-8 mutant mice, suggesting that receptor editing is defective in the absence of IRF-4. The role of IRF-4 in receptor editing was further examined in B-cell-receptor (BCR) transgenic mice. Our results show that secondary rearrangement triggered by membrane-bound antigen was defective in the IRF-4-deficient mice. Our results further reveal that the defect in secondary rearrangement is more severe at the immunoglobulin lambda locus than at the kappa locus, indicating that IRF-4 is more critical for the lambda rearrangement. We provide evidence demonstrating that the expression of IRF-4 in immature B cells is rapidly induced by self-antigen and that the reconstitution of IRF-4 expression in the IRF-4 mutant immature B cells promotes secondary rearrangement. Thus, our studies identify IRF-4 as a nuclear effector of a BCR signaling pathway that promotes secondary rearrangement at the immature B-cell stage.
受体编辑是B细胞修正抗原受体并维持中枢耐受的主要方式。先前的研究表明，干扰素调节因子4（IRF-4）和IRF-8在pre-B阶段促进免疫球蛋白轻链重排和转录。在此，分析了IRF-4和-8在受体编辑中的作用。我们的结果显示，在IRF-4基因敲除小鼠而非IRF-8基因敲除小鼠中，二次重排受损，这表明在缺乏IRF-4的情况下受体编辑存在缺陷。在B细胞受体（BCR）转基因小鼠中进一步研究了IRF-4在受体编辑中的作用。我们的结果显示，在IRF-4缺陷小鼠中，由膜结合抗原触发的二次重排存在缺陷。我们的结果进一步揭示，在免疫球蛋白λ基因座处二次重排的缺陷比κ基因座处更严重，这表明IRF-4对λ重排更为关键。我们提供的证据表明，自身抗原可快速诱导未成熟B细胞中IRF-4的表达，并且在IRF-4突变的未成熟B细胞中恢复IRF-4的表达可促进二次重排。因此，我们的研究确定IRF-4是一种BCR信号通路的核效应因子，可在未成熟B细胞阶段促进二次重排。
