Abstract
The observation that the T-bet transcription factor allows tissue-specific upregulation of intracellular osteopontin (Opn-i) in plasmacytoid dendritic cells (pDCs) suggests that Opn might contribute to the expression of interferon-α (IFN-α) in those cells. Here we show that Opn deficiency substantially reduced Toll-like receptor 9 (TLR9)–dependent IFN-α responses but spared expression of transcription factor NF-κB–dependent proinflammatory cytokines. Shortly after TLR9 engagement, colocalization of Opn-i and the adaptor molecule MyD88 was associated with induction of transcription factor IRF7–dependent IFN-α gene expression, whereas deficient expression of Opn-i was associated with defective nuclear translocation of IRF7 in pDCs. The importance of the Opn–IFN-α pathway was emphasized by its essential involvement in cross-presentation in vitro and in anti–herpes simplex virus 1 IFN-α response in vivo. The finding that Opn-i selectively coupled TLR9 signaling to expression of IFN-α but not to that of other proinflammatory cytokines provides new molecular insight into the biology of pDCs.
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Acknowledgements
We thank S. Turley for critical reading; D. Laznik for technical assistance; and A. Angel for assistance with the manuscript and figures. Supported by the National Institutes of Health (AI48125 and AI12184 to H.C.; T32 CA70083 to M.L.S; and CA48126 and AI56296 to L.H.G.), the Ellison Medical Foundation (L.H.G.) and the Juvenile Diabetes Research Foundation (M.L.S.).
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Supplementary information
Supplementary Fig. 1
Activation marker expression on pDC from Opn WT and Opn-deficient mice. (PDF 82 kb)
Supplementary Fig. 2
In vitro cross-presentation by pDC and cDC. (PDF 50 kb)
Supplementary Fig. 3
IFNAR signaling licenses pDC for antigen cross-presentation. (PDF 51 kb)
Supplementary Fig. 4
Evaluation of Opn-s and Opn-i in antigen cross-presentation. (PDF 54 kb)
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Shinohara, M., Lu, L., Bu, J. et al. Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells. Nat Immunol 7, 498–506 (2006). https://doi.org/10.1038/ni1327
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DOI: https://doi.org/10.1038/ni1327
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