title: Dissection of a circulating and intrahepatic CD4(+)Foxp3(+) T-cell subpopulation in chronic hepatitis B virus (HBV) infection: a highly informative strategy for distinguishing chronic HBV infection states.
abstract: BACKGROUND
  The definition of CD4(+)Foxp3(+) regulatory T cells (Tregs) is challenging as it relates to chronic hepatitis B virus (HBV) infection. Recently, the heterogeneity of human CD4(+)Foxp3(+) T cells has been confirmed.
  
  
  METHODS
  Three circulating CD4(+)Foxp3(+) T-cell subpopulations in chronic HBV patients were identified, and their frequencies associated with clinical parameters were analyzed. Antigen specificity of Tregs was further studied.
  
  
  RESULTS
  We found that circulating and intrahepatic CD4(+)CD45RA(-)Foxp3(hi)-activated Tregs (aTregs) were selectively increased in patients with chronic active hepatitis B and acute-on-chronic liver failure (ACLF) but not in asymptomatic carriers. The aTreg frequency was strongly correlated with HBV DNA load but not liver damage. In both peripheral blood mononuclear cells and livers, ACLF patients showed a dramatically elevated frequency of interleukin 17A-secreting CD45RA(-)Foxp3(lo) nonsuppressive T cells (non-Tregs), which were shown to be associated with severe liver damage. Interestingly, an HBV core antigen (HBcAg)-derived peptide could preferentially expand CD4(+)CD25(+)Foxp3(+) T cells and aTregs in HLA-DR9(+) chronic active hepatitis B patients, and these Tregs required ligand-specific reactivation for suppressor function.
  
  
  CONCLUSIONS
  The delineation of a CD4(+)Foxp3(+) T-cell subpopulation is a highly informative strategy for distinguishing different chronic HBV infection states. HBcAg-derived peptides may be responsible for activation of Tregs that, in turn, specifically inhibit anti-HBV immune response but not liver inflammation.
authors.affiliation: Institute of Immunology PLA, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Mengjun
authors.initials: M
authors.lastname: Zhang
authors.forename: Jijun
authors.initials: J
authors.lastname: Zhou
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhao
authors.forename: Guangyu
authors.initials: G
authors.lastname: Huang
authors.forename: Yulong
authors.initials: Y
authors.lastname: Tan
authors.forename: Shun
authors.initials: S
authors.lastname: Tan
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Niu
authors.forename: Gang
authors.initials: G
authors.lastname: Meng
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Chen
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shang
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Ni
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D004279:DNA, Viral / Q000097:blood; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D019562:Viral Load; D014766:Viremia
chemical_list: D004279:DNA, Viral; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006512:Hepatitis B Core Antigens