Sciammas Roger, Shaffer A L, Schatz Jonathan H, Zhao Hong, Staudt Louis M, Singh Harinder
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Immunity. 2006 Aug;25(2):225-36. doi: 10.1016/j.immuni.2006.07.009.
Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4(-/-) B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4(-/-) B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.
同种型转换与浆细胞分化之间协调的分子机制目前仍知之甚少。我们发现，干扰素调节因子4（IRF-4）通过控制分别编码活化诱导胞苷脱氨酶（AID）和B淋巴细胞诱导成熟蛋白1（Blimp-1）的Aicda和Prdm1基因的表达来调节这两个过程。全基因组分析表明，Irf4基因敲除（-/-）的B细胞无法诱导整个依赖Blimp-1的浆细胞程序。在Irf4（-/-）B细胞中恢复AID或Blimp-1的表达分别促进了同种型转换或分泌。IRF-4在分化的B细胞中呈梯度表达，并靶向Prdm1。较高浓度的IRF-4诱导Prdm1，从而促使从生发中心基因表达程序向浆细胞基因表达程序转变。我们提出了一个基因调控网络，其中IRF-4的梯度表达在发育过程中协调同种型转换与浆细胞分化。
