Huang Ang, Zhang Bo, Yan WeiWei, Wang Bo, Wei HuaFeng, Zhang Fan, Wu Lang, Fan KeXing, Guo YaJun
Cancer Center, Chinese People's Liberation Army General Hospital, Beijing 100853, People's Republic of China; Department of Liver Diseases, Beijing 302 Hospital, Beijing 100039, People's Republic of China;
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, People's Republic of China; and.
J Immunol. 2014 Dec 1;193(11):5461-9. doi: 10.4049/jimmunol.1400849. Epub 2014 Oct 24.
Although myeloid-derived suppressor cells (MDSCs) are well known for their immunosuppressive function in several pathological conditions, the role of MDSCs in hepatitis B virus infection remains obscure. In this study, we investigated the frequency and function of MDSCs in the peripheral blood and liver of 91 chronic hepatitis B (CHB) patients. A higher percentage of MDSCs, defined as CD14(+)HLA-DR(-/low), was detected in peripheral blood of CHB patients than that of the healthy controls. Moreover, high expression of programmed death 1 (PD-1) and secretion of IL-10 in this population were determined. The frequency of MDSCs was positively correlated with serum viral load, but it was negatively correlated with liver inflammatory injury. These cells were also abundant in liver tissue of CHB patients and were related to necroinflammatory activity. Furthermore, we found that these cells could suppress hepatitis B virus-specific CD8(+) T cell response, including reduced proliferation and IFN-γ production, and inhibit degranulation of CD8(+) T cells, including reduced production of granzyme B and perforin. Importantly, PD-1-induced IL-10 production by MDSCs was responsible for the suppressive activity. To our knowledge, for the first time our study proved that CD14(+)HLA-DR(-/low)PD-1(+) MDSCs in CHB patients contribute to an inadequate immune response against the virus and lead to chronic infection, which represents a potential target for therapeutic intervention.
尽管髓系来源的抑制性细胞（MDSCs）在多种病理状况下的免疫抑制功能已广为人知，但MDSCs在乙型肝炎病毒感染中的作用仍不清楚。在本研究中，我们调查了91例慢性乙型肝炎（CHB）患者外周血和肝脏中MDSCs的频率及功能。定义为CD14(+)HLA-DR(-/low)的MDSCs在外周血中的比例，CHB患者高于健康对照。此外，还测定了该群体中程序性死亡1（PD-1）的高表达及IL-10的分泌。MDSCs的频率与血清病毒载量呈正相关，但与肝脏炎症损伤呈负相关。这些细胞在CHB患者的肝组织中也很丰富，且与坏死性炎症活动有关。此外，我们发现这些细胞可抑制乙型肝炎病毒特异性CD8(+) T细胞反应，包括增殖减少和IFN-γ产生减少，并抑制CD8(+) T细胞的脱颗粒，包括颗粒酶B和穿孔素产生减少。重要的是，PD-1诱导MDSCs产生IL-10是其发挥抑制活性的原因。据我们所知，我们的研究首次证明CHB患者中CD14(+)HLA-DR(-/low)PD-1(+) MDSCs导致针对病毒的免疫反应不足并导致慢性感染，这代表了一个潜在的治疗干预靶点。
