title: Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity.
abstract: Having successfully developed mechanisms to evade immune clearance, hepatitis C virus (HCV) establishes persistent infection in approximately 75%-80% of patients. In these individuals, the function of HCV-specific CD8+ T cells is impaired by ligation of inhibitory receptors, the repertoire of which has expanded considerably in the past few years. We hypothesized that the coexpression of the negative regulatory receptors T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) and programmed death 1 (PD-1) in HCV infection would identify patients at risk of developing viral persistence during and after acute HCV infection. The frequency of PD-1-Tim-3- HCV-specific CTLs greatly outnumbered PD-1+Tim-3+ CTLs in patients with acute resolving infection. Moreover, the population of PD-1+Tim-3+ T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account for lack of immune control of persistent pathogens, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado Denver, Denver, Colorado, USA.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: McMahan
authors.forename: Lucy
authors.initials: L
authors.lastname: Golden-Mason
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.forename: Brian J
authors.initials: BJ
authors.lastname: McMahon
authors.forename: Michael
authors.initials: M
authors.lastname: Kemper
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: David R
authors.initials: DR
authors.lastname: Gretch
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016022:Case-Control Studies; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor