Herbert Irving Comprehensive Cancer Center, 2 Department of Pathology and Cell Biology, and 3 Department of Microbiology and Immunology, Columbia University, New York, NY 10032.
J Exp Med. 2013 Dec 16;210(13):2887-902. doi: 10.1084/jem.20131026. Epub 2013 Dec 9.
The transcription factor interferon regulatory factor-4 (IRF4) is expressed in B cells at most developmental stages. In antigen-activated B cells, IRF4 controls germinal center formation, class-switch recombination, and the generation of plasma cells. Here we describe a novel function for IRF4 in the homeostasis of mature B cells. Inducible deletion of irf4 specifically in B cells in vivo led to the aberrant accumulation of irf4-deleted follicular B cells in the marginal zone (MZ) area. IRF4-deficient B cells showed elevated protein expression and activation of NOTCH2, a transmembrane receptor and transcriptional regulator known to be required for MZ B cell development. Administration of a NOTCH2-inhibitory antibody abolished nuclear translocation of NOTCH2 in B cells within 12 h and caused a rapid and progressive disintegration of the MZ that was virtually complete 48 h after injection. The disappearance of the MZ was accompanied by a transient increase of MZ-like B cells in the blood rather than increased B cell apoptosis, demonstrating that continued NOTCH2 activation is critical for the retention of B cells in the MZ. Our results suggest that IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression. These findings may have implications for the understanding of B cell malignancies with dysregulated IRF4 and NOTCH2 activity.
转录因子干扰素调节因子-4（IRF4）在大多数发育阶段的 B 细胞中表达。在抗原激活的 B 细胞中，IRF4 控制生发中心形成、类别转换重组和浆细胞生成。在这里，我们描述了 IRF4 在成熟 B 细胞稳态中的一个新功能。体内特异性在 B 细胞中诱导 irf4 缺失导致滤泡 B 细胞在边缘区（MZ）区域的异常积累。IRF4 缺陷 B 细胞表现出 NOTCH2 蛋白表达和激活的升高，NOTCH2 是一种已知对 MZ B 细胞发育所必需的跨膜受体和转录调节剂。NOTCH2 抑制性抗体的给药在 12 小时内使 B 细胞内的 NOTCH2 核易位消失，并导致 MZ 的迅速和进行性瓦解，在注射后 48 小时几乎完全消失。MZ 的消失伴随着血液中类似 MZ 的 B 细胞的短暂增加，而不是 B 细胞凋亡的增加，这表明持续的 NOTCH2 激活对于 B 细胞在 MZ 中的保留是至关重要的。我们的结果表明，IRF4 通过调节 NOTCH2 表达来控制成熟 B 细胞在淋巴样微环境中的定位。这些发现可能对理解具有失调的 IRF4 和 NOTCH2 活性的 B 细胞恶性肿瘤具有重要意义。
