2. Academic Validation
  3. 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

  • J Immunol. 2015 Nov 15;195(10):4873-83. doi: 10.4049/jimmunol.1501362.
Zhong Fang 1,  Jin Li 2,  Xiaoyu Yu 2,  Dandan Zhang 2,  Guangxu Ren 2,  Bisheng Shi 2,  Cong Wang 2,  Anna D Kosinska 2,  Sen Wang 2,  Xiaohui Zhou 2,  Maya Kozlowski 3,  Yunwen Hu 4,  Zhenghong Yuan 5
Affiliations

Affiliations

  • 1 Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China; Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China; and.
  • 2 Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
  • 3 Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
  • 4 Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China; zhyuan@shaphc.org ywhu@shaphc.org.
  • 5 Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China; Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China; and zhyuan@shaphc.org ywhu@shaphc.org.
PMID: 26416274 DOI: 10.4049/jimmunol.1501362
Abstract

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.

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