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

Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Background:

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.

Objective:

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.

Methods:

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.

Results:

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.

Conclusions:

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
DOI: 10.1002/art.28272

Abstract Supplement

Meeting Menu

2010 ACR/ARHP