基于CD4+CD25+Treg受体Axl及其诱生下调脓毒症二重感染的实验研究

脓毒症致病过程中，机体的免疫功能受抑，导致二重感染的发生率显著增加，已经成为脓毒症治疗的新难题。研究证实，脓毒症中CD4+CD25+调节性T细胞（Treg）免疫抑制活性显著增强，是脓毒症免疫麻痹形成的关键环节，但其机理尚不清楚，且缺乏有效的干预手段。项目组前期发现，酪氨酸激酶受体Axl表达于CD4+CD25+Treg，但在初始T淋巴细胞中不表达。此外，激活Axl能够增强Treg的免疫抑制活性，提示初始T淋巴细胞向Treg分化诱导了Axl受体产生，且在Treg免疫抑制活性强化中发挥重要作用。本项目拟从整体动物水平、细胞水平和分子水平三个层次探讨CD4+CD25+Treg分化过程中受体Axl的诱生机制，分析阻断Axl受体及其诱生对脓毒症CD4+CD25+Treg免疫抑制活性和二重感染的影响。本项目将从全新角度认识免疫麻痹形成的机理，并为脓毒症二重感染防治提供新的途径和线索。

Sepsis is a life-threatening systemic inflammatory response resulted from microbial infection. It is well known that sepsis usually cause only a transient pro-inflammatroy period followed by a more prolonged period of immune suppression. Sepsis induced immunosuppression is a major factor in the host’s susceptibility to secondary infections. In sepsis, CD4+CD25+Treg cell activity increased and was associated with decreased Th1 pro-inflammatory response, contributing to sepsis-induced immunoparalysis, but the mechanism remains largely elusive. Axl is a receptor tyrosine kinase that plays multiple roles in tumorigenesis and metastasis of many cancers. Axl was not expression in normal T lymphocytes, but our previous study observed the expression of Axl in CD4+CD25+Tregs. Moreover, Axl receptor activation can enhance the suppressive activity of CD4+CD25+Tregs by upregulating the expression of CTLA-4 and Foxp3, and may play a great role in sepsis-induced immunoparalysis and secondary infections. Therefore, the mechanism of Axl expression in Treg differentiation, and the effect of inhibiting Axl and its generation on sepsis-induced immunoparalysis as well as secondary infections will be investigate in this project. This project would help to further study the mechanism of immunoparalysis in sepsis, and provide a new strategy for controlling the suppression acitivity of Treg and secondary infection after sepsis.