title: IFN-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes is promoted by NK cells via MIP-1β and LFA-1.
abstract: Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-α production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-α production by pDCs stimulated with RNA-containing IC (RNA-IC) consisting of anti-RNP autoantibodies and U1 small nuclear ribonucleoprotein particles was recently shown to be inhibited by monocytes, but enhanced by NK cells. The inhibitory effect of monocytes was mediated by TNF-α, PGE(2), and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-α production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC-induced IFN-α production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-α production. We found that CD56(dim) NK cells could increase IFN-α production >1000-fold after RNA-IC activation, whereas CD56(bright) NK cells required costimulation by IL-12 and IL-18 to promote IFN-α production. NK cells produced MIP-1α, MIP-1β, RANTES, IFN-γ, and TNF-α via RNA-IC-mediated FcγRIIIA activation. The IFN-α production in pDCs was promoted by NK cells via MIP-1β secretion and LFA-mediated cell-cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC-induced IFN-α production, which could be restored by exogenous IL-12 and IL-18. Thus, different molecular mechanisms can mediate the NK cell-dependent increase in IFN-α production by RNA-IC-stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK-pDC axis in IFN-α-driven autoimmune diseases such as SLE should be investigated.
authors: Section of Rheumatology, Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden. niklas.hagberg@medsci.uu.se
authors: Niklas
authors: N
authors: Hagberg
authors: Olof
authors: O
authors: Berggren
authors: Dag
authors: D
authors: Leonard
authors: Gert
authors: G
authors: Weber
authors: Yenan T
authors: YT
authors: Bryceson
authors: Gunnar V
authors: GV
authors: Alm
authors: Maija-Leena
authors: ML
authors: Eloranta
authors: Lars
authors: L
authors: Rönnblom
mesh_terms: D000936:Antigen-Antibody Complex / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D054407:Chemokine CCL4 / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D012313:RNA / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; D001324:Autoantigens; D054407:Chemokine CCL4; D016898:Interferon-alpha; D016169:Lymphocyte Function-Associated Antigen-1; D012313:RNA