title: Toll-Like Receptor 2 Modulates the Balance of Regulatory T Cells and T Helper 17 Cells in Chronic Hepatitis C.
abstract: Regulatory T cells (Tregs) and interleukin-17-producing T helper (Th17) cells were mutually antagonistic in the pathogenesis of chronic hepatitis C virus (HCV) infection. However, the regulation of imbalance between Tregs and Th17 cells was poorly understood in HCV infection. A recent report revealed the immunomodulatory role of Toll-like receptor (TLR) 2 in regulating the balance of Tregs/Th17 functions in multiple sclerosis. Thus, the aim of the current study was to assess the effect of TLR2 stimulation on the suppressive function of Tregs and Th17 differentiation in chronic hepatitis C. A total of 65 patients with chronic hepatitis C receiving pegylated interferon-a2a and ribavirin therapy for 48 weeks, as well as 20 of normal controls (NCs) were enrolled. Cellular proliferation and cytokine production was tested in purified CD4(+)CD25(+)CD127(dim/-) Tregs in response to the stimulation of Pam3Csk4, an agonist of TLR2. In treatment-naive patients, Tregs, but not Th17 cells, from chronic hepatitis C patients expressed higher levels of TLR2 compared with NCs. Stimulation with Pam3Csk4 enhanced the suppressive function of Tregs and production of IL-10 in chronic hepatitis C more than in NCs. However, TLR2 stimulation did not promote Th17 differentiation of Tregs in chronic hepatitis C patients. Moreover, effective anti-HCV therapy resulted in the induction of IL-17-secreting phenotypic shift of Tregs without loss of inhibitive function upon TLR2 stimulation. These data provided a novel mechanism underlying modulating the balance of Tregs/Th17 cells in chronic hepatitis C. HCV infection shifted Tregs/Th17 cells through TLR2 stimulation by inducing Tregs to produce IL-10 and enhancing inhibitive function of effector T cells, resulting in viral persistence.
authors.affiliation: 1 Department of Clinical Laboratory Medicine, the Affiliated Hospital to Changchun University of Chinese Medicine , Changchun, China .
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: 2 Department of Blood Transfusion, the Affiliated Hospital to Changchun University of Chinese Medicine , Changchun, China .
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Guan
authors.affiliation: 1 Department of Clinical Laboratory Medicine, the Affiliated Hospital to Changchun University of Chinese Medicine , Changchun, China .
authors.forename: Ben-Chun
authors.initials: BC
authors.lastname: Jiang
authors.affiliation: 3 Class of Undergraduation, College of Medicine, Jilin University , Changchun, China .
authors.forename: Zhen-Sheng-Nan
authors.initials: ZS
authors.lastname: Li
authors.affiliation: 1 Department of Clinical Laboratory Medicine, the Affiliated Hospital to Changchun University of Chinese Medicine , Changchun, China .
authors.forename: Guang-Ze
authors.initials: GZ
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D011994:Recombinant Proteins; D051195:Toll-Like Receptor 2; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a