Murine Plasmacytoid Dendritic Cells Produce IFN-γ upon IL-4 Stimulation

Suto, Akira; Nakajima, Hiroshi; Tokumasa, Naoki; Takatori, Hiroaki; Kagami, Shin-ichiro; Suzuki, Kotaro; Iwamoto, Itsuo

doi:10.4049/jimmunol.175.9.5681

Cited by 19 publications

(13 citation statements)

References 47 publications

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“…To examine the requirement for pDCs in innate protection against ivag HSV-2 challenge, pDCs were depleted by systemic injection of the pDC-specific Ab 120G8 (16) before infection. In accordance with previous studies (16,24,32,33), injection of 120G8 resulted in ϳ80% pDC depletion (data not shown). In parallel, we examined the importance of innate recognition of HSV-2 via TLR9 in vivo, in providing innate resistance to mucosal viral challenge.…”

Section: Pdcs Provide Protection From Genital Hsv-2 Infectionsupporting

confidence: 93%

Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ

Lund

Linehan

Iijima

et al. 2006

The Journal of Immunology

157

136

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Dendritic cells (DCs) are powerful APCs capable of activating naive lymphocytes. Of the DC subfamilies, plasmacytoid DCs (pDCs) are unique in that they secrete high levels of type I IFNs in response to viruses but their role in inducing adaptive immunity remains divisive. In this study, we examined the importance of pDCs and their ability to recognize a virus through TLR9 in immunity against genital HSV-2 infection. We show that a low number of pDCs survey the vaginal mucosa at steady state. Upon infection, pDCs are recruited to the vagina and produce large amounts of type I IFNs in a TLR9-dependent manner and suppress local viral replication. Although pDCs are critical in innate defense against genital herpes challenge, adaptive Th1 immunity developed normally in the absence of pDCs. Thus, by way of migrating directly into the peripheral mucosa, pDCs act strictly as innate antiviral effector cells against mucosal viral infection in situ.

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Section: Pdcs Provide Protection From Genital Hsv-2 Infectionsupporting

confidence: 93%

Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ

Lund

Linehan

Iijima

et al. 2006

The Journal of Immunology

157

136

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“…This can be explained by the fact that in addition to T cells, other sources of IFN-g found in the serum may be relevant, such as plasmacytoid DCs, 38 a cell type with known involvement in GVHD. 39 The reduced IFN-g levels in the serum could be caused by an indirect effect.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-155–deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation

Chen

Smith

Iype

et al. 2015

Blood

101

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Key Points• GVHD induction is dependent on functional miR-155 in DCs of the allo-HCT recipient.• MiR-155 deficiency reduces ATP-mediated cell migration, ERK and inflammasome activation, and IL-1b production of DCs.The successful treatment of acute leukemias with allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to determine its function in dendritic cells (DCs) during GVHD in an experimental model. We observed that miR-155 deficiency of the recipient led to improved survival, reduced serum levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition, miR-155 2/2 bone marrow chimeric mice receiving allo-HCT and miR-155 2/2 DCs showed that miR-155 deficiency in the DC compartment was responsible for protection from GVHD. Activated miR-155 2/2 DCs displayed lower expression of various purinergic receptors and impaired migration toward adenosine triphosphate (ATP). Microarray analysis of lipopolysaccharide/ATP-stimulated miR-155 2/2 DCs revealed mitogen-activated protein kinase pathway dysregulation and reduced inflammasome-associated gene expression. Consistent with this gene expression data, we observed reduced ERK activation, caspase-1 cleavage, and IL-1b production in miR-155 2/2 DCs. The connection between miR-155 and inflammasome activation was supported by the fact that Nlrp3/miR-155 double-knockout allo-HCT recipient mice had no increased protection from GVHD compared with Nlrp3 2/2 recipients. This study indicates that during GVHD, miR-155 promotes DC migration toward sites of ATP release accompanied by inflammasome activation. Inhibiting proinflammatory miR-155 by antagomir treatment could help reduce this complication of allo-HCT. (Blood. 2015;126(1):103-112)

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“…25 In brief, spleens were cut into small fragments and then digested with collagenase A (0.5 mg/mL; Roche, Indianapolis, IN) for 10 minutes at 37°C with continuous agitation. After digested fragments were filtered through a stainless-steel sieve, low-density cells were isolated by using OptiPrep reagent (Axis-Shield, Oslo, Norway).…”

Section: Isolation Of Dendritic Cells (Dcs)mentioning

confidence: 99%

“…After surface staining, cells were fixed with IC FIX (BioSource International), permeabilized with IC PERM (BioSource International), and stained with anti-IFN-␥ allophycocyanin (XMG1.2; BD PharMingen) as described previously. 25 …”

Section: Intracellular Staining For Ifn-␥mentioning

confidence: 99%

Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-γ production and the induction of Th1 cell differentiation

Tokumasa¹,

Suto

Kagami

et al. 2007

Blood

Self Cite

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It is well documented that dendritic cells (DCs), IntroductionThe differentiation and commitment of T helper (Th) cells to Th1 cells or Th2 cells depends not only on the strength of T-cell receptor and coreceptor signals provided by the direct interaction between T cells and antigen-presenting cells (APCs) but also on cytokine environment produced by the crosstalk between T cells and APCs. [1][2][3] Dendritic cells (DCs) are representative APCs 4,5 and one of the most important DC-derived cytokines for the induction of Th1 cell differentiation is IL-12. [6][7][8][9] The essential roles of IL-12 in both innate and acquired immunity are evidenced by the analysis of IL-12-deficient mice, in which NK-cell responses and Th1-cell differentiation are impaired. 10 In addition to T cells and NK cells, it has been shown that DCs themselves express a high-affinity receptor for IL-12 and can produce considerable amounts of IFN-␥ in response to These observations suggest that DCs are important sources of Th1-promoting cytokines and are thereby involved in the regulation of Th-cell differentiation.The receptor binding of cytokines results in the activation of the Janus family of protein tyrosine kinases (JAKs) and subsequently the activated JAKs phosphorylate signal transducers and activators of transcriptions (STATs). [12][13][14] There are 4 mammalian JAKs: Jak1, Jak2, Jak3, and Tyk2 and they are differentially activated in response to various cytokines. [12][13][14] From the analysis of T cells and NK cells, it has been demonstrated that IL-12 activates Jak2 and Tyk2 and then activates Stat4 that plays pivotal roles in IL-12-induced gene expression. 12-14 Analyses of Stat4-deficient (Stat4 Ϫ/Ϫ ) mice have shown that Stat4 is required for IL-12-dependent IFN-␥ production in T cells and NK cells. 15,16 Tyk2 has originally been identified as an essential molecule for mediating IFN-␣/␤ signaling 17 and subsequently has been shown to be activated in response to 18 19 [21][22][23] To address the specific and nonredundant role of Tyk2, Tyk2-deficient (Tyk2 Ϫ/Ϫ ) mice were generated, and using Tyk2 Ϫ/Ϫ mice, it has been demonstrated that Tyk2 is not essential for many of the biologic responses upon IFN-␣/␤, IL-6, and IL-10 stimulation. 23,24 In contrast, Tyk2 is required for IL-12-induced IFN-␥ production in activated T cells. 23,24 However, the role of Tyk2 in DC functions including the cytokine production and the induction of T helper cell differentiation is still largely unknown.In this study, we show that Tyk2 expression is required for IL-12, IL-23, and IFN-␥ production from DCs upon activation. We also show that Tyk2 expression in DCs is vital for the induction of antigen-specific Th1 cell differentiation. Our results indicate that Tyk2 expression in DCs is involved in the production of Th1-promoting cytokines upon activation and thereby in the induction of Th1-cell differentiation. Materials and methodsAll experiments were performed according to the guidelines of Chiba University, Chiba, Japan. MiceTyk2-deficient (Tyk2 Ϫ...

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Murine Plasmacytoid Dendritic Cells Produce IFN-γ upon IL-4 Stimulation

Cited by 19 publications

References 47 publications

Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ

Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ

MicroRNA-155–deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation

Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-γ production and the induction of Th1 cell differentiation

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