Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance
Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance
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DOI：
10.1182/blood-2005-04-1344
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发表时间：
2005-09-15
期刊：
影响因子：
20.3
通讯作者：
Taki, S
中科院分区：
文献类型：
--
作者：
Hida, S;Tadachi, M;Taki, S
虽然已知嗜碱性粒细胞能产生白介素4(IL-4)，但这些细胞的作用仅在感染寄生虫的小鼠中或在过敏性炎症的效应期才有记录。在这里，我们显示了缺乏转录因子干扰素调节因子2(IRF-2)的幼稚小鼠，表现出信号转导和转录激活因子6(Stat6)非依赖的嗜碱性粒细胞在外周的扩张。IRF-2似乎在细胞中自主地起作用，以负向调节嗜碱性粒细胞的扩张，但不能调节嗜碱性细胞产生细胞因子。在这些小鼠中观察到了CD4(+)T细胞自发的Th2极化，而Kit基因突变导致的嗜碱性粒细胞数量的遗传减少在体内消除了这种极化。我们还发现，嗜碱性粒细胞及其衍生的IL-4在体外中性条件下对Th2的发育确实是必不可少的。此外，在Th1/Th2分化培养和随后的Th2发育过程中，IL-3的中和抑制了嗜碱性粒细胞产生IL-4。这些结果表明，在Th1/Th2分化的启动过程中，嗜碱性粒细胞起到了细胞转换器的作用，将中性的IL-3转化为Th2诱导的IL-4。因此，IRF-2对嗜碱性粒细胞数量的负调节作用对于防止幼稚动物的过度Th2极化和Th1/Th2平衡至关重要。
Although basophils are known to produce interleukin 4 (IL-4), the roles of these cells have been documented only in mice infected with parasites or in the effector phase of allergic inflammations. Here we show that naive mice lacking the transcription factor, interferon regulatory factor 2 (IRF-2), exhibited signal transducer and activator of transcription 6 (Stat6)-independent expansion of basophils in the periphery. IRF-2 appeared to act autonomously in the cells to negatively regulate the expansion of, but not cytokine production by, basophils. Spontaneous Th2 polarization of CD4(+) T cells was observed in these mice and the genetic reduction of basophil numbers by mutating the Kit gene abolished such a polarization in vivo. We also found that both basophils and IL-4 derived from them were indeed essential for Th2 development under neutral conditions in vitro. Furthermore, neutralization of IL-3 abolished IL-4 production by basophils during Th1/Th2 differentiation cultures and subsequent Th2 development. These results indicated that basophils acted as a cellular converter to turn the neutral IL-3 into the Th2-inducing IL-4 during the initiation of Th1/Th2 differentiation. Thus, the negative regulatory role of IRF-2 on the basophil population size is critically important for preventing excess Th2 polarization and the Th1/Th2 balance in naive animals.