POU2AF1在吸烟诱导的人气道上皮细胞抗原提呈功能受损中的作用和机制研究

The airway epithelial cells can present antigens to T lymphocyte via the functional expression of major histocompatibility complex-II (MHC-II) molecules such as human leukocyte antigen DR (HLA-DR) and therefore take part in the host defense function of airway epithelium against pathogens. Smoking can impair the host defense function of airway epithelium and increase the risk of respiratory tract infection, leading to acute exacerbation of chronic obstructive pulmonary disease (COPD) which is largely associated with smoking. However, the mechanism mediates this effect of smoking has not been fully understood. In our previous study, we confirmed that, POU2AF1, a transcription factor previously considered to be expressed specifically in lymphocyte, where it has immune defense functions, was expressed in airway epithelial cells, and most interestingly was down-regulated by smoking. While in lymphocyte, POU2AF1 regulates the expression of HLA-DR. So we hypothesized that, in human airway epithelial cells, the down-regulation of POU2AF1 by smoking and its regulation of HLA-DR expression mediated the smoking caused impairment of antigen presentation. To validate the hypothesis, we will investigate the effect of smoking on POU2AF1, HLA-DR expression and antigen presentation in human airway epithelial cells, confirm the regulation of POU2AF1 to HLA-DR through overexpression and knock-down of POU2AF1, and explore the effect of lentivirus mediating gene therapy of POU2AF1 in rescuing the impaired antigen presentation function by smoking, therefore, to provide new strategy and target for prevention and treatment of smoking related respiratory infection, like acute exacerbation of COPD.

气道上皮细胞可通过其表达的HLA-DR分子提呈抗原给T细胞，参与气道上皮清除病原体的宿主防御反应。吸烟会损伤这一反应，增加呼吸道感染的风险，引起吸烟相关疾病如COPD的急性加重，但介导这一效应的具体机制尚不完全清楚。前期研究证实，POU2AF1，一个曾认为的淋巴细胞特异转录因子，也在人气道上皮细胞表达，并被吸烟抑制。而在淋巴细胞中，POU2AF1可调控HLA-DR的表达。因此我们假设，在人气道上皮细胞中，POU2AF1可通过调控HLA-DR表达介导吸烟引起的上皮细胞抗原提呈功能受损。为验证假说，我们在体内外探讨人气道上皮细胞中，吸烟对POU2AF1、HLA-DR表达及抗原提呈作用的影响，通过功能获得缺失实验明确POU2AF1对HLA-DR的调控作用，进而探讨慢病毒介导的POU2AF1基因治疗对吸烟诱导的气道上皮抗原提呈能力受损的逆转作用，为防治吸烟相关疾病的呼吸道感染提供新的思路和靶点。

气道上皮细胞可通过其表达的HLA-DR分子提呈抗原给T细胞，参与气道上皮清除病原体的宿主防御反应。吸烟会损伤这一反应，增加呼吸道感染的风险，引起吸烟相关疾病如COPD的急性加重，但介导这一效应的具体机制尚不完全清楚。以前研究发现在淋巴细胞中，POU2AF1可调控HLA-DR的表达。本研究明确了在中国汉族人群的气道上皮细胞中POU2AF1 和 HLA-DR 分子的表达可被吸烟抑制，并且POU2AF1 和HLA-DR 分子的表达水平具有正相关性。研究成功建立吸烟刺激人气道上皮细胞的体外模型，明确了吸烟对气道上皮细胞 POU2AF1和HLA-DR 分子表达具有抑制作用。这一模型的建立，为进一步研究吸烟引起相关疾病的发病机制及寻找可能的干预靶点提供了良好的研究工具。研究通过慢病毒载体介导的基因治疗技术，发现在气道上皮细胞中 POU2AF1 的高表达可以阻止吸烟诱导的 HLA-DR 分子表达下调。这一结果可能为预防及治疗吸烟相关疾病（如 COPD ）的呼吸道感染提供新的思路和靶点。