Plasmacytoid Dendritic Cell Dichotomy: Identification of IFN-α Producing Cells as a Phenotypically and Functionally Distinct Subset

Björck, Pia; Leong, H. Xianne; Engleman, Edgar G.

doi:10.4049/jimmunol.1000454

Cited by 65 publications

(89 citation statements)

References 37 publications

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“…IFNa, mainly produced from pDCs upon exposure to viruses via TLR7 or TLR9 (38), acts directly on memory T cells, which potentiate the antigen presentation and crosspriming capacities of CD11b þ cDCs (39,40). We detected CD9 þ pDCs, which produce abundant IFNa (14), in TDLNs from mice injected with ir.LLC/SeV/GM cells ( Fig. 5C and D).…”

Section: Discussionmentioning

confidence: 85%

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

Narusawa

Inoue

Sakamoto

et al. 2014

Cancer Immunology Research

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Vaccination with irradiated granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We therefore attempted to improve the antitumor effect by identifying little-known key pathways in GM-CSF-sensitized dendritic cells (GM-DC) in tumor-draining lymph nodes (TDLN). We initially confirmed that syngeneic mice subcutaneously injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) remarkably rejected the tumor growth. Using cDNA microarrays, we found that expression levels of type I interferon (IFN)-related genes, predominantly expressed in plasmacytoid DCs (pDC), were significantly upregulated in TDLN-derived GM-DCs and focused on pDCs. Indeed, mouse experiments demonstrated that the effective induction of GM-CSF-induced antitumor immunity observed in immunocompetent mice treated with LLC/SeV/GM cells was significantly attenuated when pDCdepleted or IFNa receptor knockout (IFNAR À/À ) mice were used. Importantly, in both LLC and CT26 colon cancer-bearing mice, the combinational use of imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype, in pDCs, but decreased the ratio of CD4 þ CD25 þ FoxP3 þ regulatory T cells in TDLNs.Collectively, these findings indicate that the additional use of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the immunologic antitumor effects of GVAX therapy, shedding promising light on the understanding and treatment of GM-CSF-based cancer immunotherapy. Cancer Immunol Res; 2(6); 568-80. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 85%

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

Narusawa

Inoue

Sakamoto

et al. 2014

Cancer Immunology Research

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“…Peripheral blood pDCs were analyzed by flow cytometry for their expression of different tetraspanin proteins based on the previous finding that expression of the tetraspanin molecule CD9 distinguishes high and low IFNα-producing pDCs in mice (23). CD5 expression was also analyzed, as this molecule has been detected on a small fraction of human CD2 hi pDCs (27,28).…”

Section: Resultsmentioning

confidence: 99%

“…To explore the possibility that a population of pDCs exists in mice that is similar to human CD5 + CD81 + pDCs, we analyzed pDCs in the blood, spleen, and bone marrow of 6-to 8-wk-old healthy C57BL/6 mice. In contrast to human pDCs, mouse pDCs express B220 and PDCA-1, as well as low levels of CD11c (23,24). After gating on cells with this phenotype, we examined their expression of CD5 and CD81.…”

Section: Resultsmentioning

confidence: 99%

“…Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23)(24)(25) and humans (26)(27)(28)(29)(30). Surface expression of CD2 divides human pDCs into two distinct subsets.…”

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confidence: 99%

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A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Zhang

Gregorio

Iwahori³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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101

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Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2 hi CD5 + CD81 + pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34 + progenitors. These CD2 hi CD5 + CD81 + cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5 + CD81 + pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5 − CD81 − pDCs, human CD5 + CD81 + pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.P lasmacytoid dendritic cells (pDCs) are a distinct lineage of bone-marrow-derived cells that reside mainly in blood and lymphoid organs in the steady state, but can also be found in sites of infection, inflammation, and cancer (1). As one of the two principal lineages of dendritic cells, pDCs diverge from conventional DCs (cDCs) during maturation in the bone marrow and are recognized mainly for their rapid and massive production of type I IFN (IFNα/β) in response to viral infection (2). Although generally viewed as weak antigen-presenting cells by comparison with cDCs, pDCs interact with many types of cells, such as NK cells, cDCs, T cells, and B cells through their secretion of cytokines and chemokines in addition to type I IFN, as well as through their expression of various costimulatory molecules (3, 4). Thus, pDCs are capable of activating CD4 + helper and regulatory T cells and CD8 + cytotoxic T cells (5-16). They can also stimulate B-cell activation, differentiation into plasma cells, and antibody production through mechanisms that are not yet completely understood (17)(18)(19)(20)(21)(22).Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23-25) and humans (26-30). Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81. Unlike CD2 hi CD5 − CD81 − pDCs, CD2 hi CD5 + CD81 + pDCs fail to produce type 1 IFN but ...

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“…CD9 + Siglec-H low PDCs have demonstrated to release IFN-α, activate CTLs and trigger a protective immunity when stimulated with TLR agonists. On the other hand, CD9 -Siglec-H high PDCs produced trivial amounts of IFN-α, induced Foxp3 + CD4 + T cells and were not able to produce antitumor immunity ( Figure 2) [44].…”

Section: Mouse Dendritic Cellsmentioning

confidence: 99%

Dendritic Cells Interactions with the Immune System – Implications for Vaccine Development

Salvador¹,

Igartua²,

Pedraz³

et al. 2012

Cell Interaction

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Plasmacytoid Dendritic Cell Dichotomy: Identification of IFN-α Producing Cells as a Phenotypically and Functionally Distinct Subset

Cited by 65 publications

References 37 publications

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Dendritic Cells Interactions with the Immune System – Implications for Vaccine Development

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