CXCL13-mediated recruitment of intrahepatic CXCR5+CD8+ T cells favors viral control in chronic HBV infection
CXCL13-mediated recruitment of intrahepatic CXCR5+CD8+ T cells favors viral control in chronic HBV infection
复制标题
CXCL13介导的肝内CXCR5（）CD8（）T细胞的募集有利于慢性乙型肝炎病毒感染的病毒控制
DOI：
10.1016/j.jhep.2019.09.031
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发表时间：
2020-03-01
影响因子：
25.7
通讯作者：
Hou, Jinlin
中科院分区：
文献类型：
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作者：
Li, Yongyin;Tang, Libo;Hou, Jinlin
背景与目的：尽管CD8(+)T细胞耗尽在慢性乙肝病毒感染过程中阻碍了病毒控制，但CD8(+)T细胞池具有表型和功能的异质性。因此，CD8(+)T细胞的一个特定亚群需要进一步研究。本研究旨在分析慢性乙肝患者外周血中表达C-X-C基序趋化因子受体5(CXCR5)的CD8(+)T细胞亚群。方法：检测慢性乙肝患者外周血中表达C-X-C基序趋化因子受体5(CXCR5)的CD8(+)T细胞频率及C-X-C基序趋化因子配体13水平。给C57BL/6、IL-21受体缺陷或B细胞缺陷小鼠注射pAAV-HBV1.2质粒。结果：慢性乙肝患者CXCR5(+)CD8(+)T细胞部分耗竭，但抗病毒能力强于CXCR5(-)亚群，且CXCR5(+)CD8(+)T细胞治疗效果良好。CHB患者体内高水平的CXCL13促进了肝内CXCR5(+)CD8(+)T细胞的募集，这一亚群产生了高水平的乙肝病毒特异性干扰素(IFN)-γ和IL-21。值得注意的是，PD1(程序性死亡1)阻断和外源性IL-21促进了干扰素-γ的产生。更引人注目的是，注射CXCR5(+)CD8(+)T细胞的小鼠表现出显著的降低了乙肝表面抗原的表达。此外，IL-21受体或B细胞缺陷小鼠肝内CXCR5(+)CD8(+)T细胞产生的HBV特异性干扰素-γ受到抑制。结论：CXCL13促进CXCR5(+)CD8(+)T细胞向肝脏募集，这一亚群改善了慢性乙肝病毒感染的病毒控制。CD8(+)T细胞亚群的鉴定有助于更好地了解CD8(+)T细胞的功能，为慢性乙肝的治疗提供潜在的免疫治疗靶点。表达受体CXCR5的CD8(+)T细胞部分耗尽，但具有强大的抗病毒活性，因为它们在慢性乙肝感染中产生高水平的乙肝病毒特异性细胞因子。CXCL13在肝脏中的高表达促进了CXCR5(+)CD8(+)T细胞的募集，并建立了对乙肝病毒感染的有效免疫控制。(C)2019年欧洲肝脏研究协会。爱思唯尔出版公司(Elsevier B.V.)
Background & Aims: Although CD8(+)T cell exhaustion hampers viral control during chronic HBV infection, the pool of CD8(+)T cells is phenotypically and functionally heterogeneous. Therefore, a specific subpopulation of CD8(+)T cells should be further investigated. This study aims to dissect a subset of CD8(+)T cells expressing C-X-C motif chemokine receptor 5 (CXCR5) in chronic HBV infection.Methods: The frequency of CXCR5(+)CD8(+)T cells and the levels of C-X-C motif chemokine ligand 13 (CXCL13), a chemokine of CXCR5, were measured in patients with chronic HBV infection. C57BL/6, interleukin (IL)-21 receptor- or B cell-deficient mice were hydrodynamically injected with pAAV-HBV1.2 plasmids. Phenotype and functions of peripheral and intrahepatic CXCR5(+) and CXCR5(-)CD8(+)T cells were assessed.Results: CXCR5(+)CD8(+)T cells were partially exhausted but possessed a stronger antiviral ability than the CXCR5(-) subset in patients with chronic HBV infection; moreover, CXCR5(+)CD8(+)T cells were associated with a favorable treatment response in patients with chronic hepatitis B (CHB). High levels of CXCL13 from patients with CHB facilitated the recruitment of intrahepatic CXCR5(+)CD8(+)T cells, and this subpopulation produced high levels of HBV-specific interferon (IFN)-gamma and IL-21. Notably, PD1 (programmed death 1) blockade and exogenous IL-21 enhanced the production of IFN-gamma. More strikingly, mice injected with CXCR5(+)CD8(+)T cells showed remarkably decreased expression of HBsAg. Additionally, an impaired production of HBV-specific IFN-gamma from intrahepatic CXCR5(+)CD8(+)T cells was observed in IL-21 receptor- or B cell-deficient mice.Conclusion: CXCL13 promotes the recruitment of CXCR5(+)CD8(+)T cells to the liver, and this subpopulation improves viral control in chronic HBV infection. The identification of this unique sub- population may contribute to a better understanding of CD8(+)T cell functions and provide a potential immunotherapeutic target in chronic HBV infection.Lay summary: Exhaustion of CD8(+)T cells is an important factor in the development of chronic hepatitis B virus (HBV) infection. CD8(+)T cells expressing the receptor CXCR5 are partially exhausted, but have potent antiviral activity, as they produce high levels of HBV-specific cytokines in chronic HBV infection. Increased expression of CXCL13 within the liver facilitates the recruitment of CXCR5(+)CD8(+)T cells and establishes effective immune control of HBV infection. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V.