Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection

Honda, Kenya; Sakaguchi, Shoji; Nakajima, Chihiro; Watanabe, Ai; Yanai, Hideyuki; Matsumoto, Misako; Ohteki, Toshiaki; Kaisho, Tsuneyasu; Takaoka, Akinori; Akira, Shizuo; Seya, Tsukasa; Taniguchi, Tadatsugu

doi:10.1073/pnas.1934678100

Cited by 330 publications

(302 citation statements)

References 31 publications

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“…This result is in agreement with studies showing that type I IFN are essential for TLR3-induced gene activation [39][40][41]. As an example, the production of IL-12 is highly reduced in IFNAR-deficient mice in response to TLR3/7 stimulation, suggesting that TLR engagement induces endogenous IFN that synergize for optimal IL-12 production [9].…”

Section: Discussionsupporting

confidence: 91%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...

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Section: Discussionsupporting

confidence: 91%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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“…In addition to their cytotoxic effects on selected tumor cells, 55 type I IFNs are known to have broader effects on the immune system by influencing the function and phenotype of dendritic cells (DCs) and T cells. [56][57][58] The fact that EGFR-MSC did not suppress allogeneic MLR responses may be a favorable characteristic for their application in immunotherapy approaches.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

et al. 2005

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We have created a novel cellular vehicle for gene therapy of malignant gliomas by transfection of murine bone marrow stroma cells (MSCs) with a cDNA encoding epidermal growth factor receptor (EGFR). These cells (EGFR-MSCs) demonstrate enhanced migratory responses toward glioma-conditioned media in comparison to primary MSCs in vitro. Enhanced migration of EGFR-MSC was at least partially dependent on EGF-EGFR, PI3-, MAP kinase kinase, and MAP kinases, protein kinase C, and actin polymerization. Unlike primary MSCs, EGFR-MSCs were resistant to FasL-mediated cytotoxicity and were capable of stimulating allogeneic mixed lymphocyte reaction, suggesting EGFR-MSCs possess suitable characteristics as vehicles for brain tumor immuno-gene therapy. Following injection at various sites, including the contralateral hemisphere in the brain of syngeneic mice, EGFR-MSCs were able to migrate toward GL261 gliomas or B16 melanoma in vivo. Finally, intratumoral injection with EGFR-MSC adenovirally engineered to secrete interferon-a to intracranial GL261 resulted in significantly prolonged survival in comparison to controls. These data indicate that EGFR-MSCs may serve as attractive vehicles for infiltrating brain malignancies such as malignant gliomas.

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“…Long double-stranded RNA ( G 38 bp) could induce a nonspecific type 1 IFN response in mammalian cells, leading to arrest in transcription and cell death. DC may be particularly sensitive to doublestranded RNA via the expression of Toll-like receptor 3 [20,21], although the small-size siRNA ( X 30 nt) reportedly fail to activate the IFN-induced protein kinase R [22] or to elicit a type 1 IFN response in mammalian cells [12]. A lingering concern for siRNA transfection is that transfection reagents may alter DC viability and their induction of a type 1 IFN response.…”

Section: Discussionmentioning

confidence: 99%

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

Liu

Akasaki

et al. 2004

Eur J Immunol

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RNA interference technology has been used to modulate dendritic cell (DC) function by targeting the expression of genes such as IL-12 and NF-kB. In this paper, we demonstrate that transfection of DC with IL-10-specific double strands of small interference RNA (siRNA) resulted in potent suppression of IL-10 gene expression without inducing DC apoptosis or blocking DC maturation. Inhibition of IL-10 by siRNA was accompanied by increased CD40 expression and IL-12 production after maturation, which endowed DC with the ability to significantly enhance allogeneic T cell proliferation. IL-10 siRNA transfection did not affect MHC class II, CD86, CD83, or CD54 expression in mature DC. To further test the ability of IL-10 siRNA-treated DC to induce a T cell response, naive CD4 T cells were stimulated by autologous DC pulsed with KLH. The results indicated that IL-10 siRNA-transfected DC enhanced Th1 responses by increasing IFN-+ and decreasing IL-4 production. These findings suggest the potential for a novel immunotherapeutic strategy of using IL-10 siRNAtransfected antigen-presenting cells as vaccine delivery agents to boost the Th1 response against pathogens and tumors that are controlled by Th1 immunity.

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Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection

Cited by 330 publications

References 31 publications

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

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