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Research article2011Peer reviewedOpen access

IFN-alpha Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1 beta and LFA-1

Hagberg, Niklas; Berggren, Olof; Leonard, Dag; Weber, Gert; Bryceson, Yenan T.; Alm, Gunnar; Eloranta, Maija-Leena; Rönnblom, Lars


Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-alpha production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-alpha 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-alpha, PGE(2), and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-alpha production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC-induced IFN-alpha production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-alpha production. We found that CD56(dim) NK cells could increase IFN-alpha production > 1000-fold after RNA-IC activation, whereas CD56(bright) NK cells required costimulation by IL-12 and IL-18 to promote IFN-alpha production. NK cells produced MIP-1 alpha, MIP-1 beta, RANTES, IFN-gamma, and TNF-alpha via RNA-IC-mediated Fc gamma RIIIA activation. The IFN-alpha production in pDCs was promoted by NK cells via MIP-1 beta secretion and LFA-mediated cell-cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC-induced IFN-alpha 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-alpha production by RNA-IC-stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK-pDC axis in IFN-alpha-driven autoimmune diseases such as SLE should be investigated. The Journal of Immunology, 2011, 186: 5085-5094.

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Journal of Immunology
2011, Volume: 186, number: 9, pages: 5085-5094

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