当前位置: X-MOL 学术Gastroenterology › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Dysregulated Response of Follicular Helper T Cells to Hepatitis B Surface Antigen Promotes HBV Persistence in Mice and Associates With Outcomes of Patients
Gastroenterology ( IF 29.4 ) Pub Date : 2018-03-12 , DOI: 10.1053/j.gastro.2018.03.021
Xiaowen Wang , Qingyang Dong , Qian Li , Yuanyuan Li , Dianyuan Zhao , Jinjie Sun , Junliang Fu , Fanping Meng , Hu Lin , Junjie Luan , Biao Liu , Min Wang , Fu-Sheng Wang , Fuchu He , Li Tang

Background & Aims

Production of neutralizing antibodies against hepatitis B surface antigen (HBsAg) is dysregulated in patients with persistent hepatitis B virus (HBV) infection. We investigated mechanisms by which this immune response to the virus is disrupted and whether it can be restored to promote clearance of HBV.

Methods

Immune-competent C57BL/6N and C57BL/6J, as well as mice deficient in follicular helper T cells (Tfh-cell-deficient), B cells, or Foxp3+ T-regulatory cells (Treg cell deficient), were given hydrodynamic injections of pAAV/HBV1.2 plasmids. Some mice were given injections of sorted Tfh cells, pan-B cells, Treg cells, or a blocking antibody against CTLA4. Production of antibodies against HBsAg and clearance of HBV were assessed by flow cytometry, enzyme-linked immunosorbent assay, polymerase chain reaction, and immunohistochemical analyses. We obtained blood samples from patients with HBV infection and isolated Treg cells. We measured the ability of Treg cells to suppress production of interleukin 21 (IL21) in CD4+ T cells.

Results

Immune-competent C57BL/6N and C57BL/6J mice transfected with the plasmid encoding HBV had features of viral clearance and viral persistence observed in humans. A Tfh-cell response to HBsAg was required for clearance of HBV and was suppressed by Treg cells in mice with persistent HBV infection. Depletion of Treg cells or inhibition of Treg-cell function (with blocking antibody against CTLA4) restored the Tfh-cell response against HBsAg and clearance of HBV in mice. Impaired Tfh-cell response to HBsAg was observed in blood from patients with chronic HBV infection, responsiveness was restored by depletion of Treg cells or blocking antibody against CTLA4.

Conclusions

In studies of HBV-infected mice and blood from patients with chronic HBV infection, we found a Tfh-cell response to HBsAg of to be required for HBV clearance, and that this response was blocked by Treg cells. Inhibiting Treg-cell activity using neutralizing antibody against CTLA4 restored the ability of Tfh cells to clear HBV infection; this approach might be developed for treatment of patients with chronic HBV infection.



中文翻译:

滤泡辅助性T细胞对乙型肝炎表面抗原反应失调促进了小鼠的HBV持久性并与患者的病情相关

背景与目标

在患有持续性乙型肝炎病毒(HBV)感染的患者中,针对乙型肝炎表面抗原(HBsAg)的中和抗体的产生失调。我们研究了这种对病毒的免疫反应被破坏的机制,以及是否可以恢复该机制以促进对HBV的清除。

方法

对具有免疫功能的C57BL / 6N和C57BL / 6J以及缺乏滤泡辅助性T细胞(Tfh细胞缺陷),B细胞或Foxp3 + T调节细胞(Treg细胞缺陷)的小鼠进行了水动力注射pAAV / HBV1.2质粒。给一些小鼠注射分选的Tfh细胞,pan-B细胞,Treg细胞或针对CTLA4的封闭抗体。通过流式细胞仪,酶联免疫吸附测定,聚合酶链反应和免疫组化分析评估抗HBsAg抗体的产生和HBV清除率。我们从患有HBV感染和分离的Treg细胞的患者那里获得了血液样本。我们测量了Treg细胞抑制CD4 + T细胞中白介素21(IL21)产生的能力。

结果

用编码HBV的质粒转染的具有免疫能力的C57BL / 6N和C57BL / 6J小鼠具有在人类中观察到的病毒清除率和病毒持久性的特征。清除HBV需要对HBsAg的Tfh细胞应答,并在持续性HBV感染的小鼠体内被Treg细胞抑制。Treg细胞的耗竭或Treg细胞功能的抑制(使用针对CTLA4的封闭抗体)恢复了小鼠中针对HBsAg的Tfh细胞应答和HBV清除。在患有慢性HBV感染的患者血液中观察到Tfh细胞对HBsAg的应答受损,通过清除Treg细胞或阻断针对CTLA4的抗体可恢复应答。

结论

在对HBV感染的小鼠和慢性HBV感染患者的血液进行的研究中,我们发现HBs清除需要对HBsAg的Tfh细胞应答,并且该应答被Treg细胞阻断。使用抗CTLA4的中和抗体抑制Treg细胞的活性,可以恢复Tfh细胞清除HBV感染的能力。这种方法可能被开发用于治疗慢性HBV感染的患者。

更新日期:2018-03-12
down
wechat
bug