title: Hepatitis C virus-induced myeloid-derived suppressor cells regulate T-cell differentiation and function via the signal transducer and activator of transcription 3 pathway.
abstract: T cells play a pivotal role in controlling viral infection; however, the precise mechanisms responsible for regulating T-cell differentiation and function during infections are incompletely understood. In this study, we demonstrated an expansion of myeloid-derived suppressor cells (MDSCs), in particular the monocytic MDSCs (M-MDSCs; CD14(+) CD33(+) CD11b(+) HLA-DR(-/low) ), in patients with chronic hepatitis C virus (HCV) infection. Notably, HCV-induced M-MDSCs express high levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and interleukin-10 (IL-10) compared with healthy subjects. Blocking STAT3 signalling reduced HCV-mediated M-MDSC expansion and decreased IL-10 expression. Importantly, we observed a significant increase in the numbers of CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells following incubation of healthy peripheral blood mononuclear cells (PBMCs) with MDSCs derived from HCV-infected patients or treated with HCV core protein. In addition, depletion of MDSCs from PBMCs led to a significant reduction of Foxp3(+) Treg cells developed during chronic HCV infection. Moreover, depletion of MDSCs from PBMCs significantly increased interferon-γ production by CD4(+) T effector (Teff) cells derived from HCV patients. These results suggest that HCV-induced MDSCs promote Treg cell development and inhibit Teff cell function, suggesting a novel mechanism for T-cell regulation and a new strategy for immunotherapy against human viral diseases.
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Jun P
authors.initials: JP
authors.lastname: Ren
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Jeddidiah W D
authors.initials: JW
authors.lastname: Griffin
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Zheng D
authors.initials: ZD
authors.lastname: Morrison
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Guang Y
authors.initials: GY
authors.lastname: Li
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Gazzar
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: Shun B
authors.initials: SB
authors.lastname: Ning
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN, USA.
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D018936:Hepatitis C Antigens / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology* / Q000821:virology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000821:virology; D014758:Viral Core Proteins / Q000276:immunology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018936:Hepatitis C Antigens; C508609:IL10 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014758:Viral Core Proteins; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: hepatitis C virus; interleukin-10; myeloid-derived suppressor cells; regulatory T cells; signal transducer and activator of transcription 3