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Receptor Cross-Linking on Human Plasmacytoid Dendritic Cells Leads to the Regulation of IFN- Production¹

Stacey L. Fanning^*,, Thaddeus C. George, Di Feng^*,, Steven B. Feldman^*, Nicholas J. Megjugorac^*,, Alexander G. Izaguirre^*, and Patricia Fitzgerald-Bocarsly^2,*,

^* New Jersey Medical School and Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103; and Amnis, Seattle, WA 98121

Plasmacytoid dendritic cells (PDC) are the natural type I IFN-producing cells that produce large amounts of IFN- in response to viral stimulation. During attempts to isolate PDC from human PBMC, we observed that cross-linking a variety of cell surface receptors, including blood DC Ag (BDCA)-2, BDCA-4, CD4, or CD123 with Abs and immunobeads on PDC leads to inhibition of IFN- production in response to HSV. To understand the mechanisms involved, a number of parameters were investigated. Cross-linking did not inhibit endocytosis of soluble Ag by PDC. Flow cytometry for annexin V and activated caspase-3 indicated that PDC are not undergoing apoptosis after receptor cross-linking. Cross-linking of CD123, but not the other receptors, caused the up-regulation of costimulatory molecules CD80 and CD86, as well as the down-regulation of CD62L, indicating PDC maturation. Thus, anti-CD123 Ab may be acting similar to the natural ligand, IL-3. Anti-phosphotyrosine Ab, as well as Ab to the IFN regulatory factor, IRF-7, was used in intracellular flow cytometry to elucidate the signaling pathways involved. Tyrosine phosphorylation occurred after cross-linking BDCA-2 and BDCA-4, but not CD4. Cross-linking did not affect IRF-7 levels in PDC, however, cross-linking BDCA-2, BDCA-4, and CD4, but not CD123, inhibited the ability of IRF-7 to translocate to the nucleus. Taken together, these results suggest that cross-linking BDCA-2, BDCA-4, and CD4 on PDC regulates IFN- production at the level of IRF-7, while the decrease in IFN- production after CD123 cross-linking is due to stimulation of the IL-3R and induction of PDC maturation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI26806 (to P.F.-B.) and a fellowship from the Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey (to S.L.F.).

² Address correspondence and reprint requests to Dr. Patricia Fitzgerald-Bocarsly, Department of Pathology and Laboratory Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103. E-mail address: bocarsly{at}umdnj.edu

³ Abbreviations used in this paper: PDC, plasmacytoid dendritic cell; BDCA, blood DC Ag; NP-1, neuropilin-1; VEGF, vascular endothelial growth factor; IRF, IFN regulatory factor; MOI, multiplicity of infection; MDDC, monocyte-derived DC; 7-AAD, 7-aminoactinomycin D; IPC, IFN--producing cell; MFI, mean fluorescence intensity; SLE, systemic lupus erythematosus; IIF, IFN--inducing factor.

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