title: IL-35 inhibits HBV antigen-specific IFN-γ-producing CTLs in vitro.
abstract: Interleukin (IL)-35 is an inhibitory cytokine consisting of IL-12A and Epstein-Barr virus-induced gene 3 (Ebi3) and is required by regulatory T-cells (Tregs) for maximal activity. During chronic hepatitis B virus (HBV) infection, Tregs have immunosuppressive effects on HBV-specific T helper (Th) cells, yet little is known about the complex regulation of Tregs and their contribution to the inadequate immune system response to the virus. In the present study, we investigated whether IL-35 is involved in HBV-related cellular immune responses. Cluster of differentiation (CD)4(+) T-cells from peripheral blood were derived from healthy volunteers, resolved HBV individuals and chronic active hepatitis B patients and stimulated with CD3/28-conjugated beads. We analysed mRNA and protein levels of IL-35 and assessed the inhibitory effect of IL-35 on HBV core antigen-specific cytotoxic T lymphocytes (CTLs), dendritic cells (DCs) and effector T-cells (Teffs). Correlation analyses between liver inflammation and HBV DNA load were conducted. Results show that chronic HBV patients harbour significantly higher levels of Ebi3 mRNA and protein in CD4(+) T-cells compared with healthy volunteers and resolved HBV individuals. IL-35 suppressed the proliferation of HBV antigen-specific CTLs and interferon (IFN)-γ production in vitro. Ex vivo, IL-35 decreased the proliferation of CD4(+)CD45RA(+) naïve T-cells, especially in CD4(+)CD25(-)CD45RA(+) naïve Teffs. IL-35 inhibited the expansion of CD11c(+) DCs. Our data indicate that IL-35 is highly expressed in chronic HBV CD4(+) T-cells and plays an important role in the inhibition of the cellular immune response in chronic HBV.
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Xuefen
authors: X
authors: Li
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Li
authors: L
authors: Tian
authors: Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Yuejiao
authors: Y
authors: Dong
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Qiaoyun
authors: Q
authors: Zhu
authors: Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Yiyin
authors: Y
authors: Wang
authors: Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Wenzheng
authors: W
authors: Han
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors: Xia
authors: X
authors: Liu
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China.
authors: Qin
authors: Q
authors: Ni
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China zychenyu@126.com ljli@zju.edu.cn.
authors: Yu
authors: Y
authors: Chen
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China zychenyu@126.com ljli@zju.edu.cn.
authors: Lanjuan
authors: L
authors: Li
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004279:DNA, Viral / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D015778:Minor Histocompatibility Antigens; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019562:Viral Load
chemical_list: D004279:DNA, Viral; C097732:EBI3 protein, human; C573415:IFNG protein, human; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; C532417:interleukin-35, human; D007371:Interferon-gamma
keywords: Chronic hepatitis B; hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs); immune response; interleukin-35; regulatory T-cells