title: Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression.
abstract: The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8+ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.
authors.affiliation: Emory University School of Medicine, 954 Gatewood Road N.E., Atlanta, GA 30329, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Radziewicz
authors.forename: Chris C
authors.initials: CC
authors.lastname: Ibegbu
authors.forename: Marina L
authors.initials: ML
authors.lastname: Fernandez
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Workowski
authors.forename: Kamil
authors.initials: K
authors.lastname: Obideen
authors.forename: Mohammad
authors.initials: M
authors.lastname: Wehbi
authors.forename: Holly L
authors.initials: HL
authors.lastname: Hanson
authors.forename: James P
authors.initials: JP
authors.lastname: Steinberg
authors.forename: David
authors.initials: D
authors.lastname: Masopust
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: John D
authors.initials: JD
authors.lastname: Altman
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D019562:Viral Load
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D053699:Interleukin-7 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor