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.
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.
Jinushi
Masahisa
M
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Takehara
Tetsuo
T
Tatsumi
Tomohide
T
Yamaguchi
Shinjiro
S
Sakamori
Ryotaro
R
Hiramatsu
Naoki
N
Kanto
Tatsuya
T
Ohkawa
Kazuyoshi
K
Hayashi
Norio
N
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
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