Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression
Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression
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DOI：
10.1073/pnas.1301138111
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发表时间：
2014-03-04
影响因子：
11.1
通讯作者：
Leonard, Warren J.
中科院分区：
文献类型：
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作者：
Liao, Wei;Spolski, Rosanne;Leonard, Warren J.
白细胞介素9（IL-9）是γ（c）家族细胞因子，其由辅助性T细胞9（Th 9）高度产生并调节一系列免疫应答，包括过敏性炎症。在这里，我们表明IL-2-JAK 3-STAT 5信号传导是Th 9分化所需的，在IL-9（编码IL-9的基因）启动子中具有关键的STAT 5结合位点。IL-2还抑制B细胞淋巴瘤6（BCL 6）的表达，并且BCL 6的过表达损害Th 9分化。相比之下，IL-21诱导野生型T细胞中的BCL 6和减少IL-9的表达，而非Bcl 6（-/-）细胞，并且IL 21（-/-）和IL 21 r（-/-）T细胞中的Th 9分化增加。有趣的是，BCL 6结合在许多STAT 5和STAT 6结合位点附近，包括在Il 9启动子处。此外，在用针对IL-2和IL-2受体的阻断抗体处理的细胞中，在该位点处存在增加的BCL 6和减少的STAT结合，这表明可能存在影响IL-9产生的BCL 6-STAT 5结合竞争。当细胞在IL-21存在下分化为Th 9时，BCL 6结合也增加。因此，我们的数据不仅揭示了IL-2通过STAT 5在IL-9基因上的直接作用，而且揭示了IL-2和IL-21对BCL-6表达的相反作用，其中BCL-6表达的增加抑制IL-9的产生。这些数据表明了一种模型，其中增加BCL 6表达降低了有效的Th 9分化，表明了控制该过程的可能的独特方法。
Interleukin 9 (IL-9) is a gamma(c)-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2-JAK3-STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and overexpression of BCL6 impaired Th9 differentiation. In contrast, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6(-/-) cells, and Th9 differentiation was increased in Il21(-/-) and Il21r(-/-) T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6-STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process.