Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection
Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection
复制标题
乙型肝炎表面抗原对单核细胞骨髓源性抑制细胞的极化是通过 ERK/IL-6/STAT3 信号反馈介导的，并抑制慢性乙型肝炎病毒感染中 T 细胞的激活
DOI：
10.4049/jimmunol.1501362
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发表时间：
2015-11-15
影响因子：
4.4
通讯作者：
Yuan, Zhenghong
中科院分区：
文献类型：
--
作者：
Fang, Zhong;Li, Jin;Yuan, Zhenghong
慢性B型肝炎病毒（HBV）感染的特征是T细胞对病毒的耐受。尽管在慢性B型肝炎（CH B）患者中观察到髓源性抑制细胞（MDSC）抑制T细胞反应，但MDSC扩增的机制仍不明确。在这项研究中，慢性乙型肝炎患者中单核细胞MDSC（mMDSC）的频率显着增加，与HBsAg水平呈正相关。我们进一步发现，在体外，B型肝炎表面抗原（HBsAg）有效地促进mMDSCs的分化，并且PBMCs中的单核细胞作为祖细胞。这需要ERK/IL-6/STAT 3信号反馈的激活。重要的是，在体外由HBsAg极化的mMDSC获得了抑制T细胞活化的能力。此外，全反式维甲酸（一种MDSC靶向药物）治疗恢复了CHB患者PBMC中HBV特异性CD 4+和CD 8 + T细胞的增殖和IFN-γ产生，并阻止了小鼠模型中病毒载量的增加。总之，HBsAg通过促进单核细胞分化为mMDSC来维持HBV持续存在并抑制T细胞应答。旨在消除MDSC的治疗可能有助于破坏CHB患者的免疫抑制。
Chronic hepatitis B virus (HBV) infection is characterized by T cell tolerance to virus. Although inhibition of T cell responses by myeloid-derived suppressor cells (MDSCs) has been observed in patients with chronic hepatitis B (CHB), the mechanism for expansion of MDSCs remains ambiguous. In this study, a significant increased frequency of monocytic MDSCs (mMDSCs) was shown positively correlated to level of HBsAg in the patients with CHB. We further found hepatitis B surface Ag (HBsAg) efficiently promoted differentiation of mMDSCs in vitro, and monocytes in PBMCs performed as the progenitors. This required the activation of ERK/IL-6/STAT3 signaling feedback. Importantly, the mMDSCs polarized by HBsAg in vitro acquired the ability to suppress T cell activation. Additionally, treatment of all-trans retinoic acid, an MDSC-targeted drug, restored the proliferation and IFN-γ production by HBV-specific CD4+ and CD8+ T cells in PBMCs from patients with CHB and prevented increase of viral load in mouse model. In summary, HBsAg maintains HBV persistence and suppresses T cell responses by promoting differentiation of monocytes into mMDSCs. A therapy aimed at the abrogation of MDSCs may help to disrupt immune suppression in patients with CHB.