IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity.
IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity.
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DOI：
10.1084/jem.20131026
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发表时间：
2013-12-16
期刊：
影响因子：
--
通讯作者：
Klein U
中科院分区：
文献类型：
--
作者：
Simonetti G;Carette A;Silva K;Wang H;De Silva NS;Heise N;Siebel CW;Shlomchik MJ;Klein U
转录因子IRF4通过抑制NOTCH2信号传导来限制B细胞在边缘区的保留。转录因子干扰素调节因子-4 （IRF4）在B细胞的大多数发育阶段都有表达。在抗原活化的B细胞中，IRF4控制生发中心的形成、类转换重组和浆细胞的产生。在这里，我们描述了IRF4在成熟B细胞内稳态中的一种新功能。体内B细胞诱导irf4特异性缺失导致irf4缺失的滤泡B细胞在边缘区（MZ）区域异常积聚。irf4缺陷B细胞显示蛋白表达升高和NOTCH2的激活，NOTCH2是MZ B细胞发育所需的跨膜受体和转录调节因子。NOTCH2抑制抗体在12小时内消除了B细胞中NOTCH2的核易位，并在注射后48小时引起MZ的快速和进行性解体。MZ的消失伴随着血液中MZ样B细胞的短暂增加，而不是B细胞凋亡的增加，这表明NOTCH2的持续激活对MZ中B细胞的保留至关重要。我们的研究结果表明，IRF4通过调节NOTCH2的表达来控制成熟B细胞在淋巴微环境中的定位。这些发现可能有助于理解IRF4和NOTCH2活性失调的B细胞恶性肿瘤。
The transcription factor IRF4 limits the retention of B cells in the marginal zone by inhibiting NOTCH2 signaling. 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.
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DOI：
10.1126/science.1213368
发表时间：
2012-06-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Khalil AM;Cambier JC;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
64.8
作者：
Dominguez-Sola, David;Ying, Carol Y.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo
DOI：
10.1084/jem.20110921
发表时间：
2011-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fabbri G;Rasi S;Rossi D;Trifonov V;Khiabanian H;Ma J;Grunn A;Fangazio M;Capello D;Monti S;Cresta S;Gargiulo E;Forconi F;Guarini A;Arcaini L;Paulli M;Laurenti L;Larocca LM;Marasca R;Gattei V;Oscier D;Bertoni F;Mullighan CG;Foá R;Pasqualucci L;Rabadan R;Dalla-Favera R;Gaidano G
通讯作者：
Gaidano G
影响因子：
4.4
作者：
Holl, Eda K.;O'Connor, Brian P.;Ting, Jenny P. -Y.
通讯作者：
Ting, Jenny P. -Y.
影响因子：
20.3
作者：
Hampel, Franziska;Ehrenberg, Stefanie;Zimber-Strobl, Ursula
通讯作者：
Zimber-Strobl, Ursula