Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-alpha/beta on antigen cross-presentation.
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.
Longman
Randy S
RS
Rockefeller University, New York, NY, USA.
Braun
Deborah
D
Pellegrini
Sandra
S
Rice
Charles M
CM
Darnell
Robert B
RB
Albert
Matthew L
ML
D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D053633:Receptor, Interferon alpha-beta; D050794:STAT1 Transcription Factor / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta