Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.
Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.
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DOI：
10.4049/jimmunol.1402953
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Geiger TL
中科院分区：
文献类型：
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作者：
Jones LL;Alli R;Li B;Geiger TL
大量的细胞因子如何通过少量的信号转导途径进行差异性信号传导尚未得到很好的解决。这对于IL-6和IL-10尤其如此，它们主要通过STAT 3起作用，但诱导不同的转录程序，从而交替地导致促炎和抗炎作用。在巨噬细胞中，持续至IL-10和瞬时至IL-6的信号传导的动力学差异对此至关重要。T细胞也是IL-6和IL-10的关键靶点，但这里的差异信号传导如何导致不同的细胞命运尚不清楚。我们发现，与巨噬细胞不同，信号持续时间不能解释这些细胞因子在T细胞中的独特作用。相反，幼稚、活化、活化-静息和记忆CD 4 + T细胞以活化状态依赖性方式差异表达IL-6和IL-10受体，这影响下游细胞因子效应。我们显示了STAT 3在IL-6介导的Th 17亚群成熟中的主导作用。IL-10不能支持Th 17分化，这是由于细胞因子接受性不足而不是信号质量。IL-10 R α在幼稚T细胞上的增强表达允许IL-10产生与IL-6相当的STAT 3信号，并且同样能够促进Th 17形成。类似地，幼稚T细胞IL-10 R α表达也允许IL-10模拟IL-6对Th 1/Th 2偏移和Tfh细胞分化的作用。我们的研究结果表明，在区分IL-6和IL-10信号传导的功能结果中，受体表达的调节而不是信号质量或持续时间起着关键作用，并确定了这些细胞因子在T细胞中与骨髓细胞相比的不同信号传导特性。
How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling here leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naïve, activated, activated-rested, and memory CD4+ T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation due to insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naïve T cells permits an IL-10 generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naïve T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.