Loss of Type I IFN Receptors and Impaired IFN Responsiveness During Terminal Maturation of Monocyte-Derived Human Dendritic Cells

Abstract

Type I IFNs are modulators of myeloid dendritic cell (DC) development, survival, and functional activities. Here we monitored the signal transduction pathway underlying type I IFN biological activities during in vitro maturation of human monocyte-derived DCs. IFN-inducible tyrosine phosphorylation of STAT family members was severely impaired upon LPS-induced DC maturation. This correlated with a marked reduction of both type I IFN receptor chains occurring as early as 4 h after LPS treatment. The reduced receptor expression was a post-transcriptional event only partially mediated by ligand-induced internalization/degradation. In fact, although an early and transient production of type I IFNs was observed after LPS treatment, its neutralization was not sufficient to completely rescue IFN receptor expression. Notably, neutralization of LPS-induced, endogenous type I IFNs did not interfere with the acquisition of a fully mature surface phenotype, nor did it have a significant effect on the allostimulatory properties of LPS-stimulated DCs. Overall, these data indicate that DCs strictly modulate their responsiveness to type I IFNs as part of their maturation program, underlining the importance of the IFN system in the regulation of DC physiology.

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

“…First, inhibition of IFN will facilitate early virus replication at the level of the individual cell. Second, the inhibition of signaling in these cells may disrupt the bridge between innate and adaptive immunity by compromising DC activation and/or maturation, as IFN-␣/␤ have critical roles in DC maturation, survival, and function (12). This hypothesis is supported by recent findings demonstrating inhibited maturation and T-cellstimulatory capabilities of human DC infected with DEN-2 in vitro (41).…”

“…In addition to direct antiviral effects, IFN serve as an important link between innate and adaptive immunity through their roles in the activation and maturation of antigen-presenting cells, including DC (2,12). DC are potentially important target cells for tick-borne flavivirus infections (24), although whether human DC are infected by TBE viruses has not been investigated.…”

Viral infection and Toll‐like receptor agonists induce a differential expression of type I and λ interferons in human plasmacytoid and monocyte‐derived dendritic cells

“…The kinetics of type I IFN measured in our experimental model are not reminiscent of a two-wave expression profile described in virus-infected fibroblasts, where IFN-g production is followed by a delayed induction of specific IFN- § genes [25]. Indeed, both in pDC and in MDDC, regardless of the virus used, the expression of all examined IFN was rapid and started as early as 1 to 3 h after infection, indicating that DC may differ from other cell types in the regulation of IFN production by viral infection.…”

“…Of note, the IFN- § 4 gene seems to be poorly induced. It should be noted that human IFN- § 4 is not an orthologue of the murine IFN- § 4, which has been described to be coordinately induced with IFN-g in the murine system [25]. Conversely, human IFN- § 4 would correspond to the murine IFN- § 8, which is also poorly induced by viral infection [38].…”

“…Whereas IRF-3 is expressed in all cell types, the expression of IRF-5 seems to be restricted to B cells and DC [23]. Conversely, IRF-7 gene expression is induced by IFN- § and IFN-g through the activation of the transcription factor IFN-stimulated regulatory factor 3 (ISGF-3) [24,25]. To evaluate the contribution of IRF in the expression of type I IFN and IFN-Q genes in MDDC and pDC following TLR triggering, the mRNA levels of IRF-5 and IRF-7 were determined by real-time RT-PCR using gene-specific primers (Fig.…”