title: Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection.
abstract: An excess of coinhibitory signals has been proposed to drive the T-cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA-4 and this correlates with viral load. CTLA-4 is up-regulated on those HBV-specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA-4-mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV-specific CD8 T cells but does not reprogram their CTLA-4(hi) Bim(hi) tolerogenic phenotype. Blocking CTLA-4 is able to increase the expansion of interferon gamma (IFN-γ)-producing HBV-specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti-HBV responses by either CTLA-4 or PD-L1 blockade is nonredundant.
  
  
  CONCLUSIONS
  CTLA-4 is expressed by HBV-specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA-4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T-cell exhaustion in this heterogeneous disease.
authors.affiliation: Division of Infection and Immunity, UCL, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Pooja
authors.initials: P
authors.lastname: Khanna
authors.forename: A Ross
authors.initials: AR
authors.lastname: Lopes
authors.forename: Ki Jun
authors.initials: KJ
authors.lastname: Han
authors.forename: Dimitra
authors.initials: D
authors.lastname: Peppa
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Micco
authors.forename: Gaia
authors.initials: G
authors.lastname: Nebbia
authors.forename: Patrick T F
authors.initials: PT
authors.lastname: Kennedy
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Geretti
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dusheiko
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D005260:Female; D019694:Hepatitis B, Chronic / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human