脓毒症时中性粒细胞PD-L1上调机制及其负向调控CD4+T细胞功能的作用研究

项目名称： 脓毒症时中性粒细胞PD-L1上调机制及其负向调控CD4+T细胞功能的作用研究

项目编号： No.81201493

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 王嘉锋

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 免疫抑制是脓毒症死亡率高的主要原因之一，本单位前期研究证实共抑制分子PD-L1在其中发挥重要作用。中性粒细胞PD-L1表达情况较少被关注，我们预实验发现其在脓毒症时高表达，机制不详。同时发现脓毒症时中性粒细胞表达MHC-Ⅱ类分子，且PD-L1+中性粒细胞内IL-10水平升高，提示脓毒症时中性粒细胞可与CD4+T细胞相关联并发挥免疫抑制作用。因此，本项目拟首先研究PD-L1+中性粒细胞的数量和功能状态及其与CD4+T细胞功能失调的相关性，并探讨其PD-L1上调的机制；然后从接触与非接触两个角度研究PD-L1+中性粒细胞对CD4+T细胞功能的影响并明确PD-L1和IL-10是其中的关键分子；最后通过同种异体回输技术在体验证脓毒症小鼠PD-L1+中性粒细胞对CD4+T细胞功能的影响。最终明确脓毒症时中性粒细胞PD-L1上调机制及其对CD4+T细胞功能的负向调控作用，阐明脓毒症免疫抑制的新机制。

中文关键词： 脓毒症；免疫抑制；中性粒细胞；程序性死亡配体1；

英文摘要： Immunosuppression is one of the main causes of high mortality during sepsis, and previous study of a member in our group demonstrated that co-inhibitory molecule PD-L1 is important for sepsis-induced immunosuppression. PD-L1 expression on neutrophils is seldom reported. Our preliminary study demonstrated that neutrophils express high level of PD-L1 during sepsis, but the mechanism is unclear. Meanwhile, we found in the preliminary study that neutrophils expressed MHC-Ⅱ class molecules and PD-L1+ neutrophils produced more IL-10. Thus we speculated that neutrophils might interactive with CD4+ T cells and negatively regulate their function during sepsis. The present study will first investigate the number and function of PD-L1+ neutrophils as well as its correlation with CD4+ T cell dysfunction; the mechanism of PD-L1 upregulation will also be studied; in vitro experiments will be performed to identify the regulatory effects of PD-L1+ neutrophils on CD4+ T cells via contact or non-contact mechanism, in which PD-L1 and IL-10 were the key molecules; finally, the role of PD-L1+ neutrophils from CLP mice on CD4+ T cell function will be validated by in vivo studies; so that the mechanism of PD-L1 upregulation on neutrophils and the negative regulatory effects of PD-L1+ neutrophils on CD4+ T cells will be clarified. This

英文关键词： sepsis；immunosuppression；neutrophils；PD-L1；