title: Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection.
abstract: NK cells are potent activators of dendritic cells (DCs), but it remains obscure how third-party cells affect the ability of NK cells to modulate DC functions. We show here that NK cells derived from healthy donors (N-NK), when cocultured with human liver epithelial cells, induced maturation as well as activation of DCs, such as increased migratory capacity as well as T cell stimulatory activity. In contrast, NK cells from chronic hepatitis C virus-infected donors (HCV-NK) were not capable of activating DCs under the same conditions. In comparison to N-NK, HCV-NK showed higher expression of CD94/NKG2A and produced IL-10 and TGFbeta when cultured with hepatic cells, most of which express HLA-E, a ligand for CD94/NKG2A. Blockade of NKG2A restored the ability of HCV-NK to activate DCs, which appeared to result from the reduced NK cell production of IL-10 and TGFbeta. The blockade also endowed HCV-NK with an ability to drive DCs to generate Th1-polarized CD4+ T cells. These findings show that NK cell modulation of DCs is regulated by third-party cells through NK receptor and its ligand interaction. Aberrant expression of NK receptors may have an impact on the magnitude and direction of DC activation of T cells under pathological conditions, such as chronic viral infection.
authors.affiliation: Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002474:Cell-Free System / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D006680:HLA Antigens / Q000096:biosynthesis / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000276:immunology; D013491:Suppressor Factors, Immunologic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D000097625:HLA-E Antigens
chemical_list: D015703:Antigens, CD; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D016753:Interleukin-10; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D013491:Suppressor Factors, Immunologic; D016212:Transforming Growth Factor beta; D000097625:HLA-E Antigens; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human