Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
NK Cells Regulate the IFN- Production by Plasmacytoid Dendritic Cells Via Soluble Factors and Cell-Cell Contact.
Hagberg2, Niklas, Berggren2, Olof, Alm1, Gunnar V., Eloranta2, Maija-Leena, Ronnblom2, Lars
Overactivation of the type I IFN system has been demonstrated in patients with SLE and several other autoimmune diseases. We previously showed that the IFN-a production by pDCs stimulated with RNA-containing immune complex (RNA-IC) was regulated by NK cells and monocytes. NK cells enhanced the IFN-a production, while monocytes inhibited the NK cell stimulation of pDCs. The suppressive effect of monocytes was largely due to ROS, PGE2 and TNF-a, while the mechanisms for NK cell enhancement were hitherto unknown.
This study was performed to investigate the mechanisms whereby NK cells promote the IFN-a production by RNA-IC-stimulated pDCs. Furthermore, NK cells from SLE patients were also investigated for their capacity to enhance the IFN-a production.
pDCs and NK cells were isolated from PBMCs of healthy blood donors or SLE patients and stimulated with RNA-IC consisting of purified U1 snRNP and IgG from an SLE patient. Concentrations of IFN-a and 16 other cytokines in cell culture supernatants from pDCs, NK cells or cocultivations of pDCs and NK cells were determined using single or multiplex immunoassays.
Soluble factors which could enhance the IFN-a production from RNA-IC stimulated pDCs were produced after FcgRIII-ligation or IL-12/IL-18 stimulation of NK cells. MIP-1a(CCL3), MIP-1b(CCL4), RANTES (CCL5), IFN-g and TNF-a were found in the cell culture supernatants from FcgR-stimulated NK cells and MIP-1b was identified as partially responsible for the NK cell-mediated increase in IFN-a production. In addition, cell-cell contact via LFA-1 also contributed to the NK cell enhancement of IFN-a production by pDCs. When NK cells and pDCs were co-cultivated, the production of several other cytokines implicated in the pathogenesis of SLE, e.g. IL-6, IFN-g and TNF-a, were also increased. NK cells from SLE patients and healthy blood donors were compared for their ability to promote the RNA-IC induced IFN-a production by pDCs. SLE NK cells were less stimulatory compared to NK cells from healthy blood donors when co-cultivated with pDCs and RNA-IC (p=0,004). However, addition of IL-12/IL-18 made the SLE NK cells as efficient as NK cells from healthy blood donors in enhancing the IFN-a production by pDCs.
This study describes novel mechanisms involved in the cross-talk between NK cells and pDCs which regulates the production of IFN-a. Both soluble factors such as MIP-1b and cell-cell-contact between NK cells and pDCs via LFA-1 were found to promote the IFN-a production. In addition, the regulatory function that NK cells exert on pDCs is altered in SLE patients. These results are of importance for understanding molecular mechanisms behind the increased IFN-a production in several autoimmune diseases and also indicate new potential therapeutic targets.
To cite this abstract, please use the following information:
Hagberg, Niklas, Berggren, Olof, Alm, Gunnar V., Eloranta, Maija-Leena, Ronnblom, Lars; NK Cells Regulate the IFN- Production by Plasmacytoid Dendritic Cells Via Soluble Factors and Cell-Cell Contact. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :503