烟草烟雾暴露下Tim-3调控CD4+T淋巴细胞介导COPD/肺气肿发生的作用及机制研究

CD4+T cell dysregulation induced by cigarette smoking is an important mechanism for the amplification and persistence of inflammation of COPD; little is known,however,about the complex mechanisms underlying the CD4+T cell dysregulation in this context. In our previous studies,CD4+T cell dysregulation was found afer cigarette smoke exposure. Recent data also suggest that Tim-3 may be a key molecule invoved in the balance between T cell activation and inhibition in COPD/emphysema. Additionally, the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3. Base on these findings, we speculate that Tim-3 induced by IL-27/NFIL3 signaling axis may involve in the immune regulation of CD4+ T cell subsets in COPD. In the current study, we first investigate the expression and the direct contribution of Tim-3 in COPD, explore the mechanisms of Tim-3 on CD4+T cell subsets dysfunction, and further assess the role of IL-27/NFIL3 signaling axis in the regulation of Tim-3 expression.This study will further elucidate the pathogenesis of cigarette smoke-induced COPD/emphysema and provide new therapeutic targets and strategies for early prevention and treatment of COPD.

吸烟诱导的CD4+辅助性T淋巴细胞免疫失衡是COPD慢性炎症持续放大的重要机制，然而其调控作用远未阐明。我们的前期工作以及最新的文献报道显示烟草烟雾暴露下CD4+辅助性T淋巴细胞免疫失衡，Tim-3在CD4+T淋巴细胞上表达减低；IL-27通过NFIL3调控Tim-3的表达。据此，我们推测，烟草烟雾暴露下IL-27/NFIL3信号轴介导的Tim-3参与调控CD4+T淋巴细胞反应导致COPD/肺气肿发生发展。本项目首先观察Tim-3在烟草烟雾暴露下COPD/肺气肿发生中的作用，研究烟草烟雾暴露下Tim-3 对CD4+辅助性T淋巴细胞免疫失衡的调控，进一步探讨IL-27/NFIL3信号轴对烟草烟雾暴露下Tim-3表达的影响。以阐明烟草烟雾暴露下COPD/肺气肿的免疫发病机制，为COPD的早期防治提供新的有效的思路和治疗靶点。

香烟烟雾诱导的CD4+辅助性T淋巴细胞免疫失衡是COPD慢性炎症持续放大的重要机 制，但其具体的调控机制尚不明确。本项目主要探讨香烟烟雾刺激下，免疫抑制分子Tim-3在吸烟相关COPD/肺气肿发生中的影响，及其对CD4+T淋巴细胞分化和功能的作用与分子机制。结果显示：1、香烟烟雾刺激下，COPD/肺气肿小鼠的Th1、Th17表达增加并与肺气肿严重程度正相关，Tim-3表达上调，主要表达于效应和记忆CD4+T细胞，且Tim-3在IFN-γ+CD4+Th1及IL-17+ Th17细胞均表达上调。烟草暴露Tim-3-/-小鼠或Tim-3中和抗体干预后，IFN-γ+Th1和IL-17+CD4+Th17表达进一步增加，肺气肿更为严重，提示Tim-3可能是调控CD4+T细胞活化与分化，Th1、Th17过度活化的重要负性分子并影响肺气肿的发展。2、体外研究发现，IL-27促进CD4+T细胞增殖并诱导IFN-γ+CD4+Th1分化，同时上调Tim-3，而重组Gal-9明显诱导IFN-γ+CD4+Th1发生凋亡。3、机制上，IL-27可能通过诱导转录因子NFIL3增加进而上调Tim-3。NFIL3-/-小鼠在烟草暴露后，CD4+T细胞Tim-3表达下调，Th1、Th17减少，肺气肿程度减轻。以上结果提示香烟烟雾刺激下，IL-27/ NFIL3/ Tim-3轴可能是调控IFN-γ+CD4+Th1、IL-17+CD4+Th17分化的重要信号分子。本研究的完成 进一步阐明了吸烟相关COPD/肺气肿的炎症特征及相关免疫机制，并为COPD免疫治疗提供干预靶点。