title: Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities.
abstract: Natural killer (NK) cells have the ability to control dendritic cell (DC)-mediated T cell responses. However, the precise mechanisms by which NK receptor-mediated regulation of NK cells determines the magnitude and direction of DC-mediated T cell responses remain unclear. In the present study, we applied an in vitro co-culture system to examine the impact of NK cells cultured with hepatic cells on DC induction of regulatory T cells. We found that interaction of NK cells and non-transformed hepatocytes (which express HLA-E) via the NKG2A inhibitory receptor resulted in priming of DCs to induce CD4(+) CD25(+) T cells with regulatory properties. NKG2A triggering led to characteristic changes of the cytokine milieu of co-cultured cells; an increase in the transforming growth factor (TGF)-beta involved in the generation of this specific type of DC, and a decrease in the tumour necrosis factor-alpha capable of antagonizing the effect of TGF-beta. The regulatory cells induced by NK cell-primed DCs exert their suppressive actions through a negative costimulator programmed death-1 (PD-1) mediated pathway, which differs from freshly isolated CD4(+) CD25(+) T cells. These findings provide new insight into the role of NK receptor signals in the DC-mediated induction of regulatory T cells.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, 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: Shinjiro
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Sakamori
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ohkawa
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C; D011971:Receptors, Immunologic / Q000276:immunology; D055607:Receptors, Natural Killer Cell; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D000097625:HLA-E Antigens
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D055654:NK Cell Lectin-Like Receptor Subfamily C; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta; D000097625:HLA-E Antigens; C527054:KLRC1 protein, human