An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T Cells.
An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T Cells.
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DOI：
10.4049/jimmunol.1500335
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发表时间：
2015-09-01
期刊：
影响因子：
--
通讯作者：
Dent AL
中科院分区：
文献类型：
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作者：
Wu H;Xu LL;Teuscher P;Liu H;Kaplan MH;Dent AL
转录因子Bcl 6是滤泡辅助性T（TFH）细胞发育所必需的。活化Stat 3的细胞因子促进Bcl 6表达和TFH细胞分化。先前的急性病毒感染模型的研究表明，TFH细胞分化减少，但在Stat 3不存在的情况下没有被阻断。本研究进一步分析了Stat 3在TFH细胞中的作用。在派伊尔集合淋巴结（PP）中，我们发现与野生型相比，Stat 3缺陷型TFH细胞的发育率低25%，并表达增加的IFNγ和IL-4。虽然PP生发中心B（GCB）细胞与Stat 3缺陷型TFH细胞以正常数量发育，但IgG 1类别转换大大增加。绵羊红细胞（SRBC）免疫后，脾脏Stat 3缺陷型TFH细胞的发育速度比对照小鼠慢，脾脏GCB细胞明显减少。Stat 3缺陷型TFH细胞在竞争性骨髓嵌合体环境中发育不良。在测试的所有条件下，Stat 3缺陷型TFH细胞过度表达IL-4和Bcl 6，这是TFH细胞群特异性的模式。最后，我们发现在体外抑制IL-4在CD 4 T细胞的表达Bcl 6需要Stat 3的功能。我们的数据表明Stat 3可以抑制TFH细胞中Bcl 6和IL-4的表达，并且Stat 3调节Bcl 6抑制靶基因的能力。总之，我们得出结论，Stat 3是需要微调TFH细胞中的多个关键基因的表达，并且特定的免疫环境决定了Stat 3在TFH细胞中的功能。
The transcription factor Bcl6 is required for the development of the follicular helper T (TFH) cells. Cytokines that activate Stat3 promote Bcl6 expression and TFH cell differentiation. Previous studies with an acute virus infection model showed that TFH cell differentiation was decreased but not blocked in the absence of Stat3. In this study, we further analyzed the role of Stat3 in TFH cells. In Peyer’s patches (PPs), we found that compared to wild-type, Stat3-deficient TFH cells developed at a 25% lower rate, and expressed increased IFNγ and IL-4. While PP germinal center B (GCB) cells developed at normal numbers with Stat3-deficient TFH cells, IgG1 class switching was greatly increased. Following immunization with Sheep Red Blood Cells (SRBC), splenic Stat3-deficient TFH cells developed at a slower rate than in control mice and splenic GCB cells were markedly decreased. Stat3-deficient TFH cells developed poorly in a competitive bone marrow chimera environment. Under all conditions tested, Stat3-deficient TFH cells over-expressed both IL-4 and Bcl6, a pattern specific for the TFH cell population. Finally, we found in vitro that repression of IL-4 expression in CD4 T cells by Bcl6 required Stat3 function. Our data indicate that Stat3 can repress the expression of Bcl6 and IL-4 in TFH cells, and that Stat3 regulates the ability of Bcl6 to repress target genes. Overall, we conclude that Stat3 is required to fine-tune the expression of multiple key genes in TFH cells, and that the specific immune environment determines the function of Stat3 in TFH cells.