title: 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.
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.
authors.affiliation: 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.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yu
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Guangxu
authors.initials: G
authors.lastname: Ren
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Bisheng
authors.initials: B
authors.lastname: Shi
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Anna D
authors.initials: AD
authors.lastname: Kosinska
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai 201508, People's Republic of China;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Kozlowski
authors.affiliation: 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.
authors.forename: Yunwen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D006509:Hepatitis B / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D015850:Interleukin-6 / Q000276:immunology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000276:immunology*
chemical_list: D006514:Hepatitis B Surface Antigens; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse