脓毒症状态下γδT细胞抗原呈递功能的改变及其分子机制的研究

The latest definition of sepsis highlights the role of dysregulated host response to infection in organ dysfunction aggravation. Maintenance of immune homeostasis of septic patients through immunotherapy is the key breakthrough to improve success rate. Antigen-presenting cell (APC) is the bridge that connects the innate and adaptive immunity. Decrease of count and function of APC has been shown to be associated with worsened clinical outcomes in patients with sepsis. Gamma-delta T cells (γδ T cells) are the newly identified population of T lymphocytes. Recent studies have found that γδ T cells possess unique and powerful antigen-presenting function, making them the hot topic in infection and cancer research. In recent years, our research team has done several research projects on the role of γδ T cells in infection. Based on the results from our recent studies, we plan to evaluate the antigen-presenting function changes of γδ T cells in septic status by analyzing the antigen-presenting related molecules on γδ T cells, antigen protein uptake ability, and their function on the proliferation and activation of CD8+ T lymphocytes. Furthermore, we will explore the mechanism and signal pathways for the APC function changes of γδ T cells. Our findings from this research could help explain the mechanism of sepsis induced immune dysfunction, enrich our understanding of the important role of γδ T cells, and build a good foundation for immunotherapy in sepsis.

脓毒症的最新定义强调机体对感染反应失调在器官功能衰竭中的作用。通过免疫干预纠正脓毒症导致的免疫失调是提高其救治成功率的关键突破口。抗原呈递细胞是连接机体固有免疫和特异免疫的桥梁，其数量和功能的下降是脓毒症患者预后不良的独立危险因素。γδT细胞是T淋巴细胞新亚类，新近的研究证实其具有独特和强大的抗原呈递功能，业已成为当今感染及肿瘤领域的研究热点。本课题组近年围绕γδT细胞在抗感染中的作用已完成多项研究工作 。本申请拟在前期工作的基础上，进一步通过先进的细胞分离、细胞共培养及流式检测等技术，研究γδT细胞在脓毒症病理状态下抗原呈递功能相关分子的表达、对外源抗原蛋白的摄取能力以及对CD8+T细胞的增殖与活化作用的变化，探索导致上述改变可能的信号通路及具体机制。所获成果有助于阐明脓毒症免疫失调的机制，丰富对γδT细胞重要功能的认识和理解，也将为脓毒症新的免疫治疗策略提供依据。

抗原递呈功能受损在脓毒症诱导的免疫抑制中起着重要的作用。近年的研究发现γδT细胞跟经典的树突状细胞类似，是专业的抗原递呈细胞，然而其在脓毒症中该功能的变化尚不清楚。本研究分析了脓毒症患者（42例）和年龄匹配的健康对照（27例）外周血γδT细胞抗原递呈功能的变化。跟健康对照相比较，脓毒症患者的γδT细胞抗原递呈相关的表面标记HLA-DR, CD27, CD80, CCR7 显著升高，提示其处于活化的状态；然而，当给予外源性磷酸化抗原HMBPP进行体外刺激，脓毒症患者的γδT细胞反应低下，表现为体外增殖能力的下降，上述抗原递呈功能相关的标记不再能活化，并且其对大肠杆菌的粘附功能降低，无法有效的刺激αβCD4细胞的增殖。上述研究结果提示，γδT细胞在脓毒症状态下可能处于过度激活的状态，再次面临抗原刺激时无法再履行其正常的抗原递呈功能，如何修复这一功能可能是缓解脓毒症所致免疫抑制新的研究方向。