Interleukin 15–dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation

Kuwajima, Seiichi; Sato, Taku; Ishida, Kazuhiko; Tada, Hiroyuki; Tezuka, Hiroyuki; Ohteki, Toshiaki

doi:10.1038/ni1348

Cited by 137 publications

(157 citation statements)

References 52 publications

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“…Although there are many type I IFNs that have been described to be produced by pDC, it is unlikely that these other type I IFNs are mediating the pDCmDC synergy because the separation of mDC and pDC by a Transwell system diminished the ability of pDC to activate mDC in vitro and to enhance T cell stimulatory capacity by mDC in vivo. Recently, several lines of evidence suggest that there is cooperation between different DC subsets in orchestrating adaptive immune responses against infectious diseases (16,36). Consistent with our findings, physical contact has been suggested to be crucial for pDC to help other DC subsets to induce appropriate adaptive immunity.…”

Section: Discussionsupporting

confidence: 91%

“…Engagement of CD2-CD2L and CD40L-CD40 interaction between pDC and lymph node DCs appear to be important mechanisms for pDC to license lymph node DCs to acquire enhanced Ag presentation activity and thereafter to prime anti-HSV CTL immunity (16). Importantly, interaction between CD40 on conventional DC and CD40L on pDC has also been recently suggested to be essential for CpG-induced immune activation against bacterial infection through IL-15-mediated mechanisms (36). Our study uses a tumor model to contribute additional evidence to the emerging concept that there is potential cross-talk between pDC and other DC types in the establishment of an Ag-specific immune response.…”

Section: Discussionmentioning

confidence: 99%

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Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses

Lou

Liu

et al. 2007

The Journal of Immunology

123

109

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Plasmacytoid dendritic cells (pDC) are capable of producing high levels of type I IFNs upon viral stimulation, and play a central role in modulating innate and adaptive immunity against viral infections. Whereas many studies have assessed myeloid dendritic cells (mDC) in the induction of antitumor immune responses, the role of pDC in antitumor immunity has not been addressed. Moreover, the interaction of pDC with other dendritic cell subsets has not been evaluated. In this study, we analyzed the capacity of pDC in stimulating an Ag-specific T cell response. Immunization of mice with Ag-pulsed, activated pDC significantly augmented Ag-specific CD8+ CTL responses, and protected mice from a subsequent tumor challenge. Immunization with a mixture of activated pDC plus mDC resulted in increased levels of Ag-specific CD8+ T cells and an enhanced antitumor response compared with immunization with either dendritic cell subset alone. Synergy between pDC and mDC in their ability to activate T cells was dependent on MHC I expression by mDC, but not pDC, suggesting that pDC enhanced the ability of mDC to present Ag to T cells. Our results demonstrate that pDC and mDC can interact synergistically to induce an Ag-specific antitumor immune response in vivo.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses

Lou

Liu

et al. 2007

The Journal of Immunology

123

109

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“…2 Thus, IL-12 is secreted as an early pro-inflammatory cytokine in response to infections. 3 Additional amplifying signals such as interferon-g (IFN-g), 4 IL-15 5 or cluster of differentiation (CD)40L-CD40 cell-cell interactions 6 are necessary for the optimal production of biologically active IL-12. Conversely, IL-12 is negatively regulated through cytokines such as IL-10 and transforming growth factor-b1 (TGF-b1).…”

Section: Open Questionsmentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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“…The expression in human mDCs is, however, less clear as some studies report weak expression (13,14), whereas a recent study shows that human mDCs contain TLR9 protein in amounts comparable with pDC (15). Moreover, intensive cross-talk between mDCs and pDCs is essential for CpG-induced immune activation in both mice and man (16,17), indicating a functional link between the DC subsets in both species.…”

Section: Introductionmentioning

confidence: 96%

In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

Nierkens¹,

Brok²,

Sutmuller³

et al. 2008

Cancer Research

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Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8 + T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1 + and LAMP-1 + compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients. [Cancer Res 2008;68(13):5390-6]

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Interleukin 15–dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation

Cited by 137 publications

References 52 publications

Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses

Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses

New insights into IL-12-mediated tumor suppression

In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

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