title: HCV-infected hepatocytes drive CD4+ CD25+ Foxp3+ regulatory T-cell development through the Tim-3/Gal-9 pathway.
abstract: HCV is remarkable at disrupting human immunity to establish chronic infection. The accumulation of Treg cells at the site of infection and upregulation of inhibitory signaling pathways (such as T-cell Ig and mucin domain protein-3 (Tim-3) and galectin-9 (Gal-9)) play pivotal roles in suppressing antiviral effector T (Teff) cells that are essential for viral clearance. While Tim-3/Gal-9 interactions have been shown to negatively regulate Teff cells, their role in regulating Treg cells is poorly understood. To explore how Tim-3/Gal-9 interactions regulate HCV-mediated Treg-cell development, here we provide pilot data showing that HCV-infected human hepatocytes express higher levels of Gal-9 and TGF-β, and upregulate Tim-3 expression and regulatory cytokines TGF-β/IL-10 in co-cultured human CD4(+)  T cells, driving conventional CD4(+)  T cells into CD25(+) Foxp3(+)  Treg cells. Additionally, recombinant Gal-9 protein can transform TCR-activated CD4(+)  T cells into Foxp3(+)  Treg cells in a dose-dependent manner. Importantly, blocking Tim-3/Gal-9 ligations abrogates HCV-mediated Treg-cell induction by HCV-infected hepatocytes, suggesting that Tim-3/Gal-9 interactions may regulate human Foxp3(+)  Treg-cell development and function during HCV infection.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Xiao J
authors.initials: XJ
authors.lastname: Ji
authors.forename: Cheng J
authors.initials: CJ
authors.lastname: Ma
authors.forename: Jia M
authors.initials: JM
authors.lastname: Wang
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.forename: Mitsumi
authors.initials: M
authors.lastname: Hirashima
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037161:Galectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta