BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms.
BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms.
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DOI：
10.1084/jem.20141380
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发表时间：
2015-04-06
期刊：
影响因子：
--
通讯作者：
Crotty S
中科院分区：
文献类型：
--
作者：
Hatzi K;Nance JP;Kroenke MA;Bothwell M;Haddad EK;Melnick A;Crotty S
Crotty和他的同事确定了BCL6在原代人滤泡T辅助细胞中的基因靶标，揭示了它作为基因抑制因子的主要作用。BCL6通过与AP1相互作用并被招募到典型的AP1结合位点，直接与一些位点结合，并与其他位点结合。滤泡辅助性T细胞（Tfh细胞）是T细胞辅助B细胞所必需的，而BCL6是Tfh细胞的决定性转录因子。然而，BCL6在Tfh细胞中的功能在很大程度上仍不清楚。本研究定义了BCL6在原代人生发中心Tfh细胞中的胞质，以评估BCL6调控CD4 T细胞的机制，比较和对比BCL6在T细胞和B细胞中的功能。BCL6主要作为Tfh细胞的抑制因子，BCL6的结合与Tfh细胞迁移的控制和其他细胞命运的抑制有关。有趣的是，尽管一些BCL6结合基因具有BCL6 DNA结合基序，但许多BCL6结合基因座的特征是存在AP1或STAT的DNA基序。AP1复合物是TCR信号传导和外部刺激的关键正向下游介质。我们发现BCL6可以直接结合AP1，并且BCL6依赖于AP1招募到具有AP1基序的BCL6结合位点，这表明BCL6破坏了AP1的活性。这些发现揭示了BCL6对Tfh生物学具有广泛和多方面的影响，并提供了这一主要调节因子如何介导不同细胞环境依赖性表型的见解。
Crotty and colleagues define the gene targets of BCL6 in primary human follicular T helper cells, revealing its primary role as a gene repressor. BCL6 bound to some loci directly and to others by interacting with AP1 and being recruited to canonical AP1-binding sites. Follicular helper T cells (Tfh cells) are required for T cell help to B cells, and BCL6 is the defining transcription factor of Tfh cells. However, the functions of BCL6 in Tfh cells have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh cells to assess mechanisms of BCL6 regulation of CD4 T cells, comparing and contrasting BCL6 function in T and B cells. BCL6 primarily acts as a repressor in Tfh cells, and BCL6 binding was associated with control of Tfh cell migration and repression of alternative cell fates. Interestingly, although some BCL6-bound genes possessed BCL6 DNA–binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6-binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology and provide insight into how this master regulator mediates distinct cell context–dependent phenotypes.
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DOI：
10.1126/science.1176676
发表时间：
2009-08-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nurieva RI;Chung Y;Martinez GJ;Yang XO;Tanaka S;Matskevitch TD;Wang YH;Dong C
通讯作者：
Dong C
影响因子：
32.4
作者：
Choi YS;Kageyama R;Eto D;Escobar TC;Johnston RJ;Monticelli L;Lao C;Crotty S
通讯作者：
Crotty S
DOI：
10.1038/nrrheum.2012.58
发表时间：
2012-05-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
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影响因子：
30.5
作者：
Butler, Noah S.;Moebius, Jacqueline;Pewe, Lecia L.;Traore, Boubacar;Doumbo, Ogobara K.;Tygrett, Lorraine T.;Waldschmidt, Thomas J.;Crompton, Peter D.;Harty, John T.
通讯作者：
Harty, John T.
影响因子：
32.4
作者：
Lee, June-Yong;Skon, Cara N.;Lee, You Jeong;Oh, Soohwan;Taylor, Justin J.;Malhotra, Deepali;Jenkins, Marc K.;Rosenfeld, M. Geoffrey;Hogquist, Kristin A.;Jameson, Stephen C.
通讯作者：
Jameson, Stephen C.