Title | Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-alpha/beta on antigen cross-presentation. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Longman RS, Braun D, Pellegrini S, Rice CM, Darnell RB, Albert ML |
Journal | Blood |
Volume | 109 |
Issue | 3 |
Pagination | 1113-22 |
Date Published | 2007 Feb 1 |
ISSN | 0006-4971 |
Keywords | 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 |
Abstract | 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. |
DOI | 10.1182/blood-2006-05-023465 |
Alternate Journal | Blood |
PubMed ID | 17018853 |
Grant List | GM07739 / GM / NIGMS NIH HHS / United States M01-RR00102 / RR / NCRR NIH HHS / United States R01 CA85784 / CA / NCI NIH HHS / United States |