title: Natural killer cells display impaired responses to toll like receptor 9 that support viral persistence in chronic hepatitis B.
abstract: Toll like receptors (TLR) are crucial mediators of innate immune responses, but their influence on natural killer (NK) cell function in chronic hepatitis B infection (CHB) is not well understood. Here we evaluated the responses of peripheral NK cells from CHB patients to multiple TLR agonists. CHB was associated with an impaired NK cell IFN-γ response to TLR9 stimulation compared to controls. This deficiency corrected with recombinant IFN-alpha, while anti-IFN-alpha neutralizing antibody diminished NK IFN-γ production in controls. NK cell CD69 upregulation in response to TLR9 was maintained in CHB. No differences were noted in responses to the other TLR ligands. Our results demonstrate a dichotomous NK cell response to TLR9 that is mediated by IFN-alpha and reflect the multiple mechanisms involved with NK activation. Consequently, it is possible that when activated these cells are unable to contribute to viral clearance while still having the potential to mediate tissue injury.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria 3168, Australia. Dilip.Ratnam@monash.edu
authors.forename: Dilip T
authors.initials: DT
authors.lastname: Ratnam
authors.forename: William
authors.initials: W
authors.lastname: Sievert
authors.forename: Kumar
authors.initials: K
authors.lastname: Visvanathan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006515:Hepatitis B virus / Q000276:immunology* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology*; D055815:Young Adult; D000099192:CD69 Antigens
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016898:Interferon-alpha; D007371:Interferon-gamma; D037181:Lectins, C-Type; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D051217:Toll-Like Receptor 9; D000099192:CD69 Antigens