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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / biosynthesis
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Antigens, CD / physiology*
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell-Free System / immunology
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Cells, Cultured
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Coculture Techniques
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Cytotoxicity, Immunologic*
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Down-Regulation / immunology*
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HLA Antigens / biosynthesis
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HLA Antigens / metabolism
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HLA-E Antigens
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Hepatitis C, Chronic / immunology*
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Hepatitis C, Chronic / metabolism
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Histocompatibility Antigens Class I / biosynthesis
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Histocompatibility Antigens Class I / metabolism
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Humans
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Immunophenotyping
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Interleukin-10 / biosynthesis
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Interleukin-10 / physiology
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K562 Cells
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism*
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Lectins, C-Type / biosynthesis
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Lectins, C-Type / physiology*
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Lymphocyte Activation / immunology
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Lymphocyte Count
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NK Cell Lectin-Like Receptor Subfamily C
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NK Cell Lectin-Like Receptor Subfamily D
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / biosynthesis
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Receptors, Immunologic / physiology*
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Receptors, Natural Killer Cell
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Signal Transduction / immunology
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Suppressor Factors, Immunologic / physiology
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / physiology
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Up-Regulation / immunology
Substances
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Antigens, CD
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HLA Antigens
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Histocompatibility Antigens Class I
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KLRC1 protein, human
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KLRD1 protein, human
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Lectins, C-Type
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NK Cell Lectin-Like Receptor Subfamily C
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NK Cell Lectin-Like Receptor Subfamily D
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Suppressor Factors, Immunologic
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Transforming Growth Factor beta
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Interleukin-10