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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1113-1122.
Prepublished online as a Blood First Edition Paper on October 3, 2006; DOI 10.1182/blood-2006-05-023465.
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Submitted May 15, 2006
Accepted September 6, 2006
Dendritic cell maturation alters intracellular signaling
networks, enabling differential effects of IFN / on antigen cross-presentation
Randy S Longman, Deborah Braun, Sandra Pellegrini, Charles Rice, Robert Darnell, and Matthew L. Albert*
Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, United States
Institut Pasteur, France
Rockefeller University, United States
INSERM AV0201, France
* Corresponding author; email: albertm{at}pasteur.fr.
The broad and often contrasting effects of type I interferons (IFN) in innate and adaptive immunity are belied by the signaling via a single receptor, IFN receptor (IFNAR). Here, we show that IFN/ induces opposing effects on the immunologic outcome of antigen cross-presentation depending on DC maturation status. Despite equivalent IFNAR expression, immature conventional dendritic cells (cDCs) activate STAT1 whereas exposure of mature DCs to IFN/ results in signaling via STAT4. Microarray analysis revealed numerous transcriptional changes resulting from the altered signaling. Importantly, STAT1 signaling resulted in significant inhibition of CD40L-induced IL-12 production, accounting for the inhibition of CD8+ T cell activation. These data provide evidence for a molecular switch in signaling pathways concomitant with DC maturation that offers a novel mechanism by which DCs modulate the integration of signals from the surrounding environment.
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