IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE. However, the underlying mechanism by which IL-6 may prevent the development of Th2-driven diseases remains unknown. Using a model of house-dust-mite (HDM)-induced Th2 differentiation and allergic airway inflammation, we show here that IL-6 signaling in allergen-specific T cells was required to prevent Th2 development and subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. Importantly, we found that IL-6 turned off IL-2 signaling during early T cell activation and thus inhibited Th2 cell priming. Mechanistically, we found that IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of suppressor of cytokine signaling 3 (SOCS3). Therapeutically, this mechanism can be mimicked by JAK1 inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions. WT and Il6-/- mice were transferred with OTII TCR-transgenic CD4+ T cells and intranasally sensitized with 100 micrograms HDM extract (endotoxin content ~250 EU/mg) + 5 micrograms of LPS-free EndoFit ovalbumin. On day 3 and day 5, OTII cells were sorted from mediastinal lymph nodes and RNA-seq was performed (three replicates). The manuscript time references start at day 0 rather than day 1.

白细胞介素-6（interleukin-6, IL-6）信号传导缺陷与辅助性T细胞2（T helper cell 2, Th2）偏倚及免疫球蛋白E（immunoglobulin E, IgE）水平升高密切相关。然而，IL-6如何阻断Th2相关疾病发生的潜在分子机制仍未明确。本研究采用屋尘螨（house dust mite, HDM）诱导的Th2细胞分化及变应性气道炎症模型，证实抗原特异性T细胞中的IL-6信号传导是阻断Th2细胞发育、后续IgE应答及变应性气道炎症的必要条件。Th2细胞谱系定型需要强且持续的白细胞介素-2（interleukin-2, IL-2）信号传导。尤为重要的是，本研究发现IL-6可在T细胞活化早期阻断IL-2信号传导，从而抑制Th2细胞的初次致敏。从机制层面来看，IL-6对活化T细胞中IL-2信号传导的抑制作用，是通过上调细胞因子信号转导抑制因子3（suppressor of cytokine signaling 3, SOCS3）实现的。在治疗层面，通过抑制Janus激酶1（Janus kinase 1, JAK1）可模拟这一机制。综上，本研究揭示了一条此前未被报道的、可阻断异常Th2细胞应答及其相关疾病发生的分子机制，并提出了潜在的预防干预策略。
将野生型（wild type, WT）及IL-6基因敲除（Il6-/-）小鼠经尾静脉注射转输OTII T细胞受体转基因CD4+ T细胞，随后以100 μg屋尘螨提取物（内毒素含量约250内毒素单位（endotoxin unit, EU）/mg）+5 μg无脂多糖（lipopolysaccharide, LPS）EndoFit卵清蛋白进行经鼻致敏。
于致敏后第3天及第5天，从小鼠纵隔淋巴结中分选OTII细胞并进行RNA测序（RNA-seq），每组设置3次生物学重复。
本文中所有时间参照均以致敏当日为第0天，而非第1天。