sE-cadherin/KLRG1信号在慢性HCV感染中抑制NK细胞功能的作用机制

It is now clear that HCV-mediated impairment of innate and adaptive immune responses is a major mechanism by which persistent infection is established. NK cells are a major component of the innate immune system. Studies indicate that NK cells play a pivotal role in the pathogenesis of acute and chronic liver disease in HCV infection. Thus, factors that control NK cell numbers and function are critical for the innate immune response. Therefore, further studies are required to understand the mechanisms involving viral persistence and antiviral response in HCV infection. Given the pivotal role of NK cells in linking innate and adaptive immunity during HCV infection, in this proposal, we will comprehensively investigate a new inhibitory receptor, Killer cell lectin-like receptor G1 (KLRG1) receptor which is considered to be a marker of terminally differentiated NK and T cells and is strongly induced by viral and other infections. The binding of KLRG1 to E-cadherin-expressing cells prevents the lysis of epithelial targets and is responsible for controlling the activation threshold of NK and T cells and thereby suppressing immune response. E-cadherin can be lost from the cell surface by proteolytic cleavage, resulting in the generation of 80 kDa fragment referred to a soluble E-cadherin (sE-cadherin). Our preliminary data demonstrated that a significant increase of KLRG1 expression on circulating NK cells in chronic HCV infectious patients compared to healthy controls, and the up-regulation expression of KLRG1 on NK cells lead to a significant impairment of antiviral functions of NK cells. We also found elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HCV viral load and liver function marker AST. Based on our preliminary studies, this proposal is designed to study the biological and clinical significance of KLRG1 expression on NK cells and serum sE-cadherin in chronic HCV infection. We will further verify whether chronic HCV infection contribute both to KLRG1 up-regulation on NK cells and increase of sE-cadherin in the serum, we'll also investigate whether systemic sE-cadherin can up-regulate the KLRG1 expression on NK cells. Then try to explore the mechanism in which sE-cadherin/KLRG1 interaction down-regulation function of NK cells and help in virus immune evasion. Completion of this study may be provide new theoretical basis for virus innate immune evasion in chronic HCV infection and provide a new potential target for immunotherapy.

自然杀伤细胞（NK细胞）是清除丙型肝炎病毒（HCV）的重要先天免疫细胞，其功能受损直接影响HCV感染的免疫病理进程。KLRG1作为NK细胞重要抑制性受体在HCV免疫逃逸及持续感染中的作用尚待研究。课题组前期工作发现慢性HCV感染时KLRG1表达上调伴随其可溶性配体sE-cadherin增高、NK细胞功能抑制，但sE-cadherin/KLRG1信号在HCV感染者NK细胞功能中的作用机制还不清楚。本项目拟结合临床资料、体外细胞培养体系及生物信息学分析：NK细胞KLRG1和血清sE-cadherin在慢性HCV感染中的表达特征及对IFN/RBV治疗效果的影响；HCV感染对sE-cadherin及NK细胞KLRG1表达的诱导机制；sE-cadherin/ KLRG1信号在调控NK细胞功能及HCV病毒免疫逃逸的作用机制及关键分子，以期为病毒免疫逃逸机制提供新的理论基础，并为临床干预提供潜在靶点。

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