Journal
JOURNAL OF IMMUNOLOGY
Volume 189, Issue 6, Pages 2735-2745Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1102038
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Funding
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI026806, AI082994, AI057468, AI076937]
- University of Medicine and Dentistry of New Jersey-Graduate School for Biomedical Sciences
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
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Plasmacytoid dendritic cells (pDC) are rare cells found in peripheral blood and lymphoid tissues. pDC are considered to be professional type I IFN-producing cells and produce 10- to 100-fold more IFN-alpha than other cell types in response to enveloped viruses or synthetic TLR7 and TLR9 agonists. In this study, purified pDC were found to express high levels of IFN-lambda receptor mRNA, as well as cell-surface IFN-lambda receptor. We have developed intracellular flow cytometry assays using Abs to IFN-lambda 1/3 or -lambda 2 to assess the expression of IFN-lambda proteins by pDC. We observed that a subset of human pDC expresses only intracellular IFN-alpha, whereas another subset produces both IFN-alpha and IFN-lambda after stimulation with virus or the TLR9 agonist, CpG A; the cells that coexpressed IFN-alpha and IFN-lambda were the cells with the highest levels of IFN-alpha expression. Ab cross-linking of CD4 or CD303 molecules on pDC inhibited both HSV-induced IFN-lambda and IFN-alpha production. Like the production of IFN-alpha, the HSV-induced IFN-lambda production in pDC was mediated through TLR9 and independent of virus replication. Exogenous IFN-lambda treatment of pDC resulted in increased virus-induced expression of both IFN-alpha and IFN-lambda. In addition, both exogenous IFN-lambda and -alpha inhibited dexamethasone-induced apoptosis of pDC. We conclude that pDC are major producers of IFN-lambda 1 and -lambda 2 in response to viral stimulation and also express functional receptors for this cytokine. Thus, IFN-lambda can serve as an autocrine signal to strengthen the antiviral response of pDC by increasing IFN-alpha and IFN-lambda production, resulting in prolonged pDC survival. The Journal of Immunology, 2012, 189: 2735-2745.
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