title: Hepatitis C virus core protein triggers expansion and activation of CD4(+)CD25(+) regulatory T cells in chronic hepatitis C patients.
abstract: CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus (HCV)-specific T-cell responses and viral persistence in HCV-infected individuals. We postulated that HCV core protein (HCVc) directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells (PBMCs) and sera were collected from 87 treatment-naïve chronic HCV-infected patients, CD4(+)CD25(+) Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. CD4(+), CD8(+), CD4(+)CD25(+) and CD4(+)CD25(-) T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor (TLR) ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4(+)CD25(+) Tregs. Mechanistic studies showed that HCVc, together with anti-CD3 antibody, augmented CD4(+)CD25(+) Treg proliferation, but inhibited CD4(+)CD25(-) T-cell proliferation and IFN-γ production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand (poly I:C) and the TLR4 ligand (lipopolysaccharide, LPS), the TLR2 ligand (lipoteichoic acid, LTA) and HCVc both inhibited TCR-induced CD4(+) T-cell proliferation and IFN-γ secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4(+)CD25(+) Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV-infected patients.
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
authors.forename: Naicui
authors.initials: N
authors.lastname: Zhai
authors.affiliation: Department of Hepatology, The First Hospital, Jilin University, Changchun, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Chi
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
authors.forename: Tianyang
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
authors.forename: Hongxiao
authors.initials: H
authors.lastname: Song
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Ian Nicholas
authors.initials: IN
authors.lastname: Crispe
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.|Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Hepatology, The First Hospital, Jilin University, Changchun, China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.|Department of Hepatology, The First Hospital, Jilin University, Changchun, China.
authors.forename: Zhengkun
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology; D061251:Primary Cell Culture; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D013682:Teichoic Acids / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D015704:CD4 Antigens; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014758:Viral Core Proteins; C009900:lipoteichoic acid; D007371:Interferon-gamma; D011070:Poly I-C