title: Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice.
abstract: OBJECTIVE
  We studied the functions of natural killer (NK) cells and the role of the NK cell inhibitory receptor (NKG2A) during hepatitis B virus (HBV) infection in patients and mice.
  
  
  METHODS
  We analyzed levels of NKG2A on peripheral blood NK cells from 42 patients with active chronic hepatitis B (CHB), 31 patients with inactive CHB, and 35 healthy volunteers (controls). Five patients with CHB treated with antiviral therapy were also included to evaluate changes in NK cells after HBV titers decreased. We examined the effects of blocking antibodies against NKG2A or its ligand Qa-1 (equivalent to HLA-E in humans) in immunocompetent mice that express HBV from a plasmid and are positive for serum hepatitis B surface antigen (a mouse model of HBV infection).
  
  
  RESULTS
  A higher percentage of NK cells from patients with active CHB were positive for NKG2A (38.47%) than from patients with inactive CHB (19.33%; P < .01) or controls (27.96%; P < .05). The percentage of NKG2A(+) cells correlated with serum viral load (r = 0.5457; P < .001). The percentage of NKG2A(+) cells decreased along with HBV load in patients that received antiviral therapy (P < .05). Blocking NKG2A interaction with HLA-E in peripheral NK cells from patients with active CHB increased their cytotoxicity in vitro. NK cells of HBV carrier mice also had higher percentages of NK cells that expressed NKG2A compared with control mice; NKG2A was likely to be up-regulated by production of interleukin-10 by hepatic regulatory CD4(+)CD25(+) T cells. Blocking Qa-1 in these mice promoted viral clearance in an NK cell-dependent manner.
  
  
  CONCLUSIONS
  Infection with HBV increases levels of the inhibitory receptor NKG2A on NK cells in mice and humans, and reduces their ability to clear HBV. Reagents designed to block the interaction between NKG2A and HLA-E might be developed to treat CHB infection.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Fenglei
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China; Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China. Electronic address: ustcwhm@ustc.edu.cn.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Long
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China; Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China. Electronic address: tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006510:Hepatitis B Antibodies / Q000032:analysis*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D063065:Organophosphonates / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D055654:NK Cell Lectin-Like Receptor Subfamily C; D063065:Organophosphonates; C032907:Q surface antigens; C053001:adefovir; D000225:Adenine