title: B and T lymphocyte attenuator is highly expressed on intrahepatic T cells during chronic HBV infection and regulates their function.
abstract: BACKGROUND
  T cell antiviral function is impaired during chronic hepatitis B (CHB). Programmed death-1 (PD-1) impairs antiviral T cell responses, but dysfunction is not always reversed by blockade of PD-1 pathway. Whether distinct T cell populations expressing different sets of inhibitory molecules exist has not been determined.
  
  
  METHODS
  We studied the expression of the B and T lymphocyte attenuator (BTLA) on both peripheral blood mononuclear cells (PBMC) and intrahepatic lymphocytes, and the effects of blocking BTLA on circulating and intrahepatic T cells in CHB patients. Sixty-three CHB patients who underwent liver biopsy were enrolled. The expression of BTLA and PD-1 on PBMC and intrahepatic T cells was assessed by flow cytometry with antibodies to T cell differentiation molecules. Functional recovery was evaluated by analyzing production of interferon (IFN)-γ and interleukin (IL)-2 after incubation of T cells with anti-CD3 and irradiated mature dendritic cells in the presence of anti-BTLA, anti-PD-1, or both.
  
  
  RESULTS
  Intrahepatic T cells expressed higher levels of BTLA than their peripheral counterparts. A significant fraction of intrahepatic T cells coexpressed BTLA and PD-1 and showed deep exhaustion of T cell responses. Blockade of the BTLA pathway enhanced both intrahepatic and PBMC T cell proliferation and cytokine secretion, and exhibited an additive effect upon blockage of PD-1.
  
  
  CONCLUSIONS
  Upregulation of inhibitory receptor BTLA restricts T cell responses in CHB. T cell exhaustion by high antigen concentrations exacerbates dysfunction of peripheral and intrahepatic T cells. Blockage of BTLA is a potential therapeutic approach for chronic HBV infection that may act by restoring antiviral T cell responses.
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, 200025, People's Republic of China, caigangsmmu@hotmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Cai
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Nie
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.forename: Beiying
authors.initials: B
authors.lastname: Wu
authors.forename: Jiafei
authors.initials: J
authors.lastname: Lin
authors.forename: Cen
authors.initials: C
authors.lastname: Jiang
authors.forename: Huaizhou
authors.initials: H
authors.lastname: Wang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
mesh_terms: D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C482586:BTLA protein, human; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D007371:Interferon-gamma