title: Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors.
abstract: OBJECTIVE
  There is an unclear relationship between inhibitory receptor expression on T cells and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is often not the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver T cells from patients with hepatitis C virus (HCV) and other viral infections.
  
  
  METHODS
  We analyzed 36 liver samples from HCV antibody-positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virological responses to treatment, and 1 from a patient with spontaneous clearance) with 19 paired blood samples and 51 liver samples from HCV-negative patients with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified for total and virus-specific T cells by flow cytometry.
  
  
  RESULTS
  Levels of the markers PD-1 and 2B4 (but not CD160, TIM-3, or LAG-3) were increased on intrahepatic T cells from healthy and diseased liver tissues compared with T cells from blood. HCV-specific intrahepatic CD8(+) T cells from patients with chronic HCV infection were distinct in that they expressed TIM-3 along with PD-1 and 2B4. In comparison, HCV-specific CD8(+) T cells from patients with sustained virological responses and T cells that recognized cytomegalovirus lacked TIM-3 but expressed higher levels of LAG-3; these cells also had different memory phenotypes and proliferative capacity.
  
  
  CONCLUSIONS
  T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and cytomegalovirus-specific CD8(+) T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Kroy
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Donatella
authors.initials: D
authors.lastname: Ciuffreda
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cooperrider
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tomlinson
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Garrett D
authors.initials: GD
authors.lastname: Hauck
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jasneet
authors.initials: J
authors.lastname: Aneja
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts.
authors.forename: Christoph
authors.initials: C
authors.lastname: Berger
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Wolski
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts; Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Divison of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.affiliation: Transplantation Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Nahel
authors.initials: N
authors.lastname: Elias
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Division of Immunology, Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: de Kruyff
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Misdraji
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: glauer@mgh.harvard.edu.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000097:blood / Q000276:immunology* / Q000821:virology; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C084093:CD244 protein, human; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family
keywords: CMV; Costimulation; HCV; IHL; Immune Regulation; Inflammation; PBMC; T-Cell Exhaustion; cytomegalovirus; hepatitis C virus; intrahepatic lymphocyte; peripheral blood mononuclear cell