|Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-alpha/beta on antigen cross-presentation.
|Year of Publication
|Longman RS, Braun D, Pellegrini S, Rice CM, Darnell RB, Albert ML
|2007 Feb 1
|Animals, Antigen Presentation, CD8-Positive T-Lymphocytes, Dendritic Cells, Gene Expression Profiling, Gene Expression Regulation, Interferon-alpha, Interferon-beta, Lymphocyte Activation, Mice, Receptor, Interferon alpha-beta, Signal Transduction, STAT1 Transcription Factor, STAT4 Transcription Factor
The broad and often contrasting effects of type I interferons (IFNs) in innate and adaptive immunity are belied by the signaling via a single receptor, IFN-alpha receptor (IFNAR). Here, we show that IFN-alpha/beta induces opposing effects on the immunologic outcome of antigen cross-presentation depending on dendritic cell (DC) maturation status. Despite equivalent IFNAR expression, immature conventional DCs (cDCs) activate STAT1 in response to IFN-alpha/beta, whereas exposure of mature DCs to IFN-alpha/beta 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.
|GM07739 / GM / NIGMS NIH HHS / United States
M01-RR00102 / RR / NCRR NIH HHS / United States
R01 CA85784 / CA / NCI NIH HHS / United States