title: Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection.
abstract: We previously reported that monocyte-derived dendritic cells activate resting NK cells by expressing MHC class I-related chain A and B (MICA/B), ligands for NKG2D, in response to IFN-alpha, but the MICA/B expression was severely impaired in patients with chronic hepatitis C virus (HCV) infection. In the present study, we examined induction of MICA/B on DCs by various innate cytokines and found that DCs from either healthy donors or HCV-infected individuals, upon IL-15 stimulation, express MICA/B and can activate NK cells, which is solely dependent on MICA/B-NKG2D interaction. Of interest is the finding that IL-15- and type I IFN-mediated induction of MICA/B in healthy donors is completely inhibited when DCs are incubated in the presence of anti-IFN-alpha/betaR or anti-IL-15Ralpha, respectively, suggesting interdependent roles of these cytokines in MICA/B expression. Indeed, DCs produced IL-15 in response to type I IFN, whereas they directly produced IFN-beta, in response to IL-15, which was followed by the production of IFN-alpha. In HCV-infected individuals, type I IFN-mediated production of IL-15 was virtually absent, but IL-15-mediated production of type I IFN was not compromised, which is consistent with the distinct ability of these cytokines to induce MICA/B in these patients. The present study demonstrates that IL-15 and type I IFN lead to DC expression of MICA/B and subsequent DC activation of NK cells, which is critically dependent on each other's autocrine/paracrine effect, and suggests that impaired IL-15 production is one of the mechanisms of the aberrant response of DC to type I IFN in HCV-infected patients.
authors: Osaka University Graduate School of Medicine, Department of Molecular Therapeutics, Suita, Osaka, Japan.
authors: Masahisa
authors: M
authors: Jinushi
authors: Tetsuo
authors: T
authors: Takehara
authors: Tomohide
authors: T
authors: Tatsumi
authors: Tatsuya
authors: T
authors: Kanto
authors: Veronika
authors: V
authors: Groh
authors: Thomas
authors: T
authors: Spies
authors: Takahiro
authors: T
authors: Suzuki
authors: Takuya
authors: T
authors: Miyagi
authors: Norio
authors: N
authors: Hayashi
mesh_terms: D019898:Autocrine Communication / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000502:physiology; D016899:Interferon-beta / Q000096:biosynthesis / Q000502:physiology; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D007399:Interphase / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019899:Paracrine Communication / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology; D055607:Receptors, Natural Killer Cell
chemical_list: D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; D016898:Interferon-alpha; D019409:Interleukin-15; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016899:Interferon-beta