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Secretion and Modulation of Immune Phenotype by Vasoactive Intestinal Peptide1
,
,
* Department of Pediatrics,
Holden Comprehensive Cancer Center, and
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Plasmacytoid dendritic cells (PDC) are considered the main sentinels against viral infections and play a major role in immune tolerance. Vasoactive intestinal peptide (VIP) is a potent immunomodulator, whose role in PDC function is unknown. The present study was designed to investigate whether human PDC express VIP receptors and whether VIP has immunological effects on PDC. Using real-time RT-PCR and immunofluorescence, we demonstrated that VIP receptors VPAC1 and VPAC2 are expressed on PDC. After culturing PDC with VIP and CpG oligodeoxynucleotides for 48 h, expression of surface molecules with significance for PDC-T cell interactions as well as IFN-
secretion were quantified using FACS analysis and ELISA, respectively. For functional assays, CFSE-stained CD4+ T cells were coincubated with differentially treated PDC. T cell proliferation and production of various cytokines were determined by FACS analysis and ELISA. VIP enhanced PDC expression of CD86, MHC II, and CCR7. In contrast, VIP inhibited PDC secretion of IFN- and expression of Neuropilin-1 and MHC I. The potential of CpG oligodeoxynucleotide-activated PDC to induce proliferation of allogeneic CD4+ T cells was impaired when VIP was present during activation. Furthermore, pretreatment of PDC with VIP resulted in a decrease of the IFN-
:IL-4 ratio in cocultured T cells, suggesting a modulation of the immune response toward Th2. Taken together, these results strongly suggest that VIP regulates the immunological function of human PDC. VIP may thus be involved in the modulation of immune responses to viral infections as well as in the maintenance of immune tolerance.
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 the Carver Research Program of Excellence, the Children’s Miracle Network, and National Institutes of Health Grant RO1 CA82691 (to M.S.O.).
2 Address correspondence and reprint requests to Dr. M. Sue O’Dorisio, Pediatric Hematology/Oncology, 375 Newton Road, 4235 Medical Education Building Research Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52242. E-mail address: sue-odorisio{at}uiowa.edu
3 Abbreviations used in this paper: VIP, vasoactive intestinal peptide; DC, dendritic cell; PDC, plasmacytoid DC; Treg, regulatory T cell; mDC, myeloid DC; ODN, oligodeoxynucleotide; CT, cycle threshold; MFI, median fluorescence intensity; CFDA-SE, carboxyfluorescein diacetate succinimidyl ester.
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