IL-6 plays a pivotal role in favoring T-cell commitment toward a Th17 cell rather than Treg-cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL-6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17-cell responses, but also enhanced Treg-cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL-6-deficient mice, with significantly stronger adaptive Th2 responses in both IL-6(-/-) mice and BALB/c recipients of neutralizing anti-IL-6 monoclonal Ab. Although IL-6-deficient mice showed lower steady-state Th17-cell levels, IL-6-independent Th17-cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg-cell phenotype however, as IL-6-deficient mice displayed reduced expression of Foxp3, Helios, and GATA-3, and enhanced production of cytokines within the Treg-cell population. Administration of an anti-IL-2:IL-2 complex boosted Treg-cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL-6-deficient mice. Thus, in vivo, IL-6 limits the Th2 response, modifies the Treg-cell phenotype, and promotes host susceptibility following helminth infection.
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机译:如通过体外模型系统建立的,IL-6在促进T细胞对Th17细胞而非Treg细胞表型的承诺中起关键作用。我们预测,在没有IL-6的情况下,感染了胃肠蠕虫Heligmosomoides polygyrus的小鼠将显示Th17细胞反应减少,但Treg细胞活性增强,因此敏感性更高。出人意料的是,蠕虫的驱除在IL-6缺陷型小鼠中显着增强,在IL-6(-/-)小鼠和中和性抗IL-6单克隆抗体的BALB / c受体中,Th2的适应性反应明显增强。尽管缺乏IL-6的小鼠显示出较低的稳态Th17细胞水平,但在体内感染期间发生了独立于IL-6的Th17细胞应答。我们排除了Th17反应作为保护因素,因为Ab中和作用不会改变BALB / c小鼠对H. polygyrus感染的免疫力。抵抗确实与相关的Treg细胞表型的显着变化相关,因为IL-6缺陷小鼠显示Foxp3,Helios和GATA-3的表达减少,并且Treg细胞群内细胞因子的产生增加。抗IL-2:IL-2复合物的给药可提高体内Treg细胞的比例,减少对WT水平的适应性Th2反应,并在IL-6缺陷型小鼠中完全恢复了对poly H. polygyrus的易感性。因此,在体内,IL-6限制了Th2反应,修饰了Treg细胞表型,并在蠕虫感染后提高了宿主易感性。
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