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, PGE2, 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 CD56dim NK cells could increase IFN-α production >1000-fold after RNA-IC activation, whereas CD56bright 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.

Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56dim NK Cells

“…Mechanistically, NK cells promoted RNA-IC-induced IFN-a secretion by pDCs via soluble factors, such as MIP-1b, and via LFA-1-dependent cell-cell interactions. In addition to IFN-a, the secretion of several cytokines and chemokines implicated in the pathogenesis of SLE (e.g., IFN-g, IL-6, IL-8, MIP-1b, and TNF-a) was also enhanced in RNA-IC-stimulated pDC-NK cell cocultures (15). Consequently, pDC-NK cell cross-talk could be important in promoting sustained type I IFN production and the inflammatory response in systemic autoimmune diseases.…”

“…Previous studies showed that NK cells interact with pDCs to potently enhance IFN-a production upon stimulation with viruses, synthetic oligonucleotides, or RNA-containing ICs (RNA-ICs) (13)(14)(15). Mechanistically, NK cells promoted RNA-IC-induced IFN-a secretion by pDCs via soluble factors, such as MIP-1b, and via LFA-1-dependent cell-cell interactions.…”

“…To investigate which cytokines could be responsible for the increased expression of CD319 and CD229, purified pDCs were cultured with or without RNA-IC stimulation and the addition of a selection of recombinant cytokines, which are either produced in pDC-NK cell cocultures (15) or known to have a stimulatory effect on pDCs (25). A weak increase in CD319 and CD229 expression on pDCs was seen after the addition of rTNF-a, rGM-CSF, and rIL-3 (Fig.…”

“…3A). Because the stimulation of pDCs by these ICs is strongly promoted by NK cells (14,15), we proceeded to investigate the regulation of CD319 and CD229 in cocultures of pDCs and NK cells. Notably, the addition of NK cells restored the upregulation of CD319 and CD229 on pDCs (Fig.…”

“…RNA-IC stimulation of pDC-NK cell cocultures induces the production of multiple cytokines that can affect both pDCs and NK cells (15). To investigate which cytokines could be responsible for the increased expression of CD319 and CD229, purified pDCs were cultured with or without RNA-IC stimulation and the addition of a selection of recombinant cytokines, which are either produced in pDC-NK cell cocultures (15) or known to have a stimulatory effect on pDCs (25).…”