title: A heterogeneous hierarchy of co-regulatory receptors regulates exhaustion of HCV-specific CD8 T cells in patients with chronic hepatitis C.
abstract: OBJECTIVE
  The functionality of virus-specific T cells is regulated by a sophisticated network of an expanding repertoire of co-regulatory receptors, which could be harnessed for immunotherapeutic applications. However, targeting particular pathways during persistent virus infections has resulted in variable outcomes. The extent to which T cell exhaustion can be reversed, by targeting multiple co-regulatory pathways, still remains not fully investigated.
  
  
  METHODS
  We analysed the phenotype and in vitro functionality of HCV-specific CD8(+) T cells expressing PD-1, CTLA-4, TIM-3 or 2B4 either alone or in various combinations and compared expression levels to those of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) specific T cells in peripheral blood mononuclear cells (PBMCs) from the same cohort of patients with chronic hepatitis C (CHC) infection.
  
  
  RESULTS
  Blockade and/or crosslinking of distinct co-regulatory pathways in exhausted HCV-specific CD8(+) T cells resulted in rather diverse and individualized T cell responses, irrespective of the type and number of receptors targeted. Overall, in vitro manipulations of these pathways yielded three response possibilities: (i) total non-response (ii) good single blockade response and (iii) good dual/multiple blockade response, with each comprising approximately one-third of the patients tested. The diversity of the in vitro responsiveness of HCV-specific T cells was reflected by an enormous ex vivo phenotypic heterogeneity. Despite this broad heterogeneity, HCV-specific CD8(+) T cells differed from EBV- and CMV-specific T cells in particular by TIM-3 expression, which also correlated with liver disease activity and viral load.
  
  
  CONCLUSIONS
  HCV-specific CD8(+) T cell functionality, upon co-regulatory receptor manipulations, was characterized by an individual pattern of responses in patients with CHC, suggesting that treatment approaches, targeting these receptors, should consider inter-individual differences and be personalized.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Solomon
authors.initials: S
authors.lastname: Owusu Sekyere
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Pothakamuri Venkata
authors.initials: PV
authors.lastname: Suneetha
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Anke Renate Maria
authors.initials: AR
authors.lastname: Kraft
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Shihong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine 1, J. W. Goethe University Hospital, Frankfurt am Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dietz
authors.affiliation: Department of Internal Medicine 1, J. W. Goethe University Hospital, Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael Peter
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: Schlaphoff.Verena@mh-hannover.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Schlaphoff
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: Cornberg.Markus@mh-hannover.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Cornberg
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: Wedemeyer.Heiner@mh-hannover.de.
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics; D019562:Viral Load; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D012367:RNA, Viral
keywords: 2B4; CMV; CTLA-4; Chronic hepatitis C; Co-regulatory receptors; EBV; HCV; PD-1; T cell exhaustion; TIM-3