CXCR5+CD8+T细胞在慢性HBV感染中对病毒控制和抗体产生的免疫机制研究

Recent studies have verified that CXCR5+CD8+T cells can mediate an imperative role in curtail chronic infection, such as HIV and LCMV, however, little is known about their role in chronic HBV infection. Our preliminary study found that the frequency of CXCR5+CD8+T cells in peripheral blood from CHB patients with virological response was significantly higher than that in CHB patients with non-virological response. Notably, compared with CXCR5-CD8+T cells, CXCR5+CD8+T cells were able to secrete significantly higher levels of interleukin-21(IL-21), a cytokine provides B cell helper signals, and antiviral cytokine IFN-γ. Based on our previous work, we hypothesized that CXCR5+CD8+T cells is a specific subset of exhausted CD8+T cell pool in chronic HBV infection. This subset owns relatively stronger reactivity and function, and may be involved in controlling HBV replication and promoting generation of HBV specific antibodies. Herein, with the help of cross-sectional cohort with chronic HBV infection and longitudinal cohort with antiviral treatment, and in combination with in vitro experiments and HBV mouse model established on CD8 knockout mice, we aim to investigate the characteristics of CXCR5+CD8+T cells in chronic HBV infection as well as during antiviral treatment. In addition, the effect of this subset on viral control and HBV specific antibodies production was also explored. This research will help to provide a better understanding of the immunological mechanisms in chronic HBV infection and a significant implication for the exploration of a CXCR5+CD8+T cell-based immunotherapy approach in treatment of chronic HBV infection.

近期研究已证实CXCR5+CD8+T细胞在控制慢性病毒（如HIV和LCMV）感染中发挥了重要作用，但其在慢性HBV感染中的作用尚未阐明。我们初步研究发现外周血CXCR5+CD8+T细胞频数在抗病毒治疗后获得病毒学应答的CHB患者中显著升高，且这群细胞分泌IFN-γ和IL-21的水平显著高于CXCR5-CD8+T细胞。结合我们前期工作基础，我们推测CXCR5+CD8+T细胞是慢性HBV感染耗竭CD8+T细胞群中具备较强反应性和功能的亚群，其可能参与控制HBV复制和促进HBV相关抗体产生。本项目拟通过慢性HBV感染人群和抗病毒治疗队列，结合体外实验以及CD8基因敲除小鼠HBV模型，探讨CXCR5+CD8+T细胞在慢性HBV感染和抗病毒治疗中的特点以及其在病毒控制和特异性抗体产生中的作用。本研究有助于深入揭示慢性HBV感染的免疫学机制，对探索以该群细胞为靶点的乙肝免疫治疗新策略具有重要意义。

乙肝表面抗原（HBsAg）消失或伴血清学转换是乙肝病毒（HBV）感染临床治愈的标志，宿主免疫在乙肝临床治愈中发挥尤为重要的作用。在本项目中我们通过慢性HBV感染横向和抗病毒治疗纵向队列，结合体外实验以及基因工程小鼠HBV模型进行研究，我们发现：（1）CXCR5+CD8+T细胞是慢性HBV感染耗竭CD8+T细胞群中具备较强反应性和功能的亚群，其抗病毒效能比CXCR5-CD8+T细胞强，主要通过分泌IFN-γ等抗病毒细胞因子以非溶细胞途径清除病毒；CXCR5+CD8+T细胞和B细胞可在肝内趋化因子CXCL13的作用下向肝脏趋化募集，通过分泌细胞因子IL-21来促进B细胞产生乙肝中和性抗体HBsAb，有利于病毒控制和乙肝治愈。（2）左旋肉碱（L-Cn）显著抑制外周血CXCR5+CD8+T细胞的功能，减低HBV小鼠模型脾脏中生发中心的形成，进而导致血清中HBsAg清除延迟。本项目的研究成果阐明了CXCR5+CD8+T细胞亚群在慢性HBV感染和抗病毒治疗中的特点和作用以及CXCR5+CD8+T细胞促进病毒控制和抗体产生的免疫机制，揭示了CXCR5+CD8+T细胞以及趋化因子CXCL13在调控乙肝治愈的重要作用，为探索乙肝免疫治疗新策略提供了新思路。