Plasmacytoid dendritic cells (pDC) have been regarded as the “professional type I IFN–producing cells” of the immune system following viral recognition that relies on the expression of TLR7 and TLR9. Furthermore, pDC link the innate and adaptive immune systems via cytokine production and Ag presentation. More recently, their ability to induce tolerance and cytotoxicity has been added to their “immune skills.” Such a broad range of actions, resembling the diverse functional features of a Swiss army knife, requires strong and prompt molecular regulation to prevent detrimental effects, including autoimmune pathogenesis or tumor escape. Over the last decades, we and other investigators have started to unravel some aspects of the signaling pathways that regulate the various functions of human pDC. In this article, we review aspects of the molecular regulatory mechanisms to control pDC function in light of their multifaceted roles during immunity, autoimmunity, and cancer.

Plasmacytoid dendritic cells (pDC), a subset of the dendritic cell (DC) family, develop from hematopoietic stem cells in the bone marrow. The intermediate progenitor cell stages of human pDC are to be defined, but mouse pDC differentiate from either common DC progenitors or lymphoid-primed multipotent progenitors (1). Human and mouse pDC development depend on Flt3 ligand (2, 3); expression of the transcription factor Spi-B, an Ets-family member controlling expression of the antiapoptotic gene Bcl2A1 (47); and the basic helix-loop-helix protein E2-2 (8, 9). pDC are key mediators of innate immunity, mainly against viruses, by sensing their nucleic acids via TLR7 and TLR9. Following TLR7/9 triggering, pDC produce large amounts of type I IFNs (IFN-α/β) that control viral replication (10). pDC also produce the proinflammatory cytokines IL-6 and TNF-α, which regulate T, B, and NK cell and conventional DC (cDC) responses, together with IFN-α/β (10). Further, pDC play a role in T cell activation because TLR ligation induces pDC maturation into so-called “pDC-derived DC” that exhibit DC morphology and Ag-presentation capacity (11). Over the past years, the molecular pathways involved in controlling pDC activation and maturation are being unraveled, uncovering new aspects of pDC functions, such as cytotoxic and tolerogenic abilities. Such pleiotropic immune abilities, similar to the features of a Swiss army knife (Fig. 1), may have detrimental effects when uncontrolled, as seen in autoimmune diseases. We review the main molecular mechanisms that should keep activated pDC “on physiological track” and highlight some aspects of deregulated pathways as observed in disease, with a particular focus on human pDC.

FIGURE 1.

pDC as the Swiss army knife of the innate immune system. Illustrated are the multifaceted functions of pDC to produce cytokines, present Ag, and induce cytotoxicity and tolerance. Taken together, pDC resemble a Swiss army knife (adapted from clipartist.net) that is equipped with multiple features.

FIGURE 1.

pDC as the Swiss army knife of the innate immune system. Illustrated are the multifaceted functions of pDC to produce cytokines, present Ag, and induce cytotoxicity and tolerance. Taken together, pDC resemble a Swiss army knife (adapted from clipartist.net) that is equipped with multiple features.

Close modal

During the first 6 h following TLR7/9 activation, pDC devote up to 60% of their transcriptome to expression of type I IFN genes (IFN-α, -β, and -ω) and type III genes (IFN-λ1–3) (12, 13). Such robust secretion capacity requires specific cellular and molecular mechanisms; as such, their “plasmacytoid” secretory morphology resembles Ab-secreting plasma cells. The rapid and substantial IFN-α/β production by pDC in response to TLR ligation is mediated by constitutive expression of the master regulator IFN response factor (IRF)7 (reviewed in Ref. 14) (Fig. 2). The signaling cascades downstream of TLR7/9 depend on the adaptor protein MyD88, which complexes with IL-1R–associated kinase (IRAK)1 and IRAK4, TNFR-associated (TRAF)6 and TRAF3, and IRF7 and IRF5 (reviewed in Ref. 14). Both TLR7/9 signaling pathways activate NF-κB depending on phosphorylation of inhibitory (I)κB proteins by the kinases IκBα and IκBβ and subsequent degradation (15, 16). Known NF-κB members are RelA/p65, RelB, cRel, p52, and p50, which form homo- or heterodimers. The RelA/p50 heterodimer is most frequently activated after TLR signaling (15). RelA/p50 dimers are directly responsible for expression of costimulatory molecules (i.e., CD40, CD80, CD86), whereas IRF5, together with NF-κB and MAPK activation, is crucial for the production of IL-6 and TNF-α (reviewed in Ref. 14). Phosphorylation of IRF7, likely mediated by PI3K activation, leads to IRF7 nuclear translocation with the help of osteopontin, which, in turn, leads to IFN-α/β gene transcription (17, 18). Auto/paracrine production of IFN-α/β promotes pDC survival via induction of antiapoptotic genes, whereas TNF-α supports pDC maturation. It is believed that ligation of TLR in the early endosomal/lysosome-related compartment will preferentially turn on IFN production, whereas late endosomal/lysosomal engagement regulates proinflammatory cytokine production and maturation (reviewed in Ref. 14) (19).

FIGURE 2.

TLR activation pathway in pDC and its regulation in health and disease. pDC selectively express TLR7 and TLR9 in the endosomal compartment. TLR activation is mediated by engagement of viral ssRNA and bacterial DNA, respectively (nonself-recognition). Self–nucleic acids, in complex with the small cationic antimicrobial peptide LL-37 are able to trigger TLR7/9 in pDC. Entry of self-DNA/LL-37 complexes also can be facilitated by plasma cell–derived autoantibodies that engage FcγRIIA. In addition, TLR7 can be activated by synthetic compounds, such as imiquimod or R848, whereas TLR9 recognizes synthetic CpG oligodeoxynucleotides, including CpG-A and CpG-B. TLR7/9 triggering leads to activation of MyD88 and downstream signaling cascade via the NF-κB pathway, IRF5/7, and MAPK. This ultimately leads to expression of type I/III IFN, proinflammatory cytokines IL-6 and TNF-α, and costimulatory molecules, such as CD40, CD80, and CD86, which are the key components of pDC-derived antiviral response and Ag presentation. In addition, pDC can exert cytotoxic properties via expression of TRAIL and GrB, which is also involved in the tolerogenic properties of pDC within the tumor environment. The different functions of pDC and the different regulators that separate the physiological aspects from the dysfunctional pDC-derived pathophysiology are listed on the right. The antiviral response is controlled primarily via microRNA regulation (miR-146a, miR-155/miR-155*); failure to do so can lead to autoimmune diseases, such as SLE, Sjögren’s syndrome, and psoriasis.

FIGURE 2.

TLR activation pathway in pDC and its regulation in health and disease. pDC selectively express TLR7 and TLR9 in the endosomal compartment. TLR activation is mediated by engagement of viral ssRNA and bacterial DNA, respectively (nonself-recognition). Self–nucleic acids, in complex with the small cationic antimicrobial peptide LL-37 are able to trigger TLR7/9 in pDC. Entry of self-DNA/LL-37 complexes also can be facilitated by plasma cell–derived autoantibodies that engage FcγRIIA. In addition, TLR7 can be activated by synthetic compounds, such as imiquimod or R848, whereas TLR9 recognizes synthetic CpG oligodeoxynucleotides, including CpG-A and CpG-B. TLR7/9 triggering leads to activation of MyD88 and downstream signaling cascade via the NF-κB pathway, IRF5/7, and MAPK. This ultimately leads to expression of type I/III IFN, proinflammatory cytokines IL-6 and TNF-α, and costimulatory molecules, such as CD40, CD80, and CD86, which are the key components of pDC-derived antiviral response and Ag presentation. In addition, pDC can exert cytotoxic properties via expression of TRAIL and GrB, which is also involved in the tolerogenic properties of pDC within the tumor environment. The different functions of pDC and the different regulators that separate the physiological aspects from the dysfunctional pDC-derived pathophysiology are listed on the right. The antiviral response is controlled primarily via microRNA regulation (miR-146a, miR-155/miR-155*); failure to do so can lead to autoimmune diseases, such as SLE, Sjögren’s syndrome, and psoriasis.

Close modal

TLR7/9 signaling needs to be counterregulated to prevent ongoing cytokine production, because this is deleterious for the host. Cell surface receptors on human pDC that dampen TLR-induced responses include the C-type lectin blood DC Ag 2 (BDCA2), DC immunoreceptor (DCIR), Ig-like transcript 7 (ILT7), FcεRI, NK protein 44, adenosine diphosphate P2Y receptors, a NO-induced cGMP-dependent receptor, and PGE2 receptors (2022). Viruses can highjack the signaling pathways downstream of such receptors and escape from immune recognition (Fig. 2). For example, the hepatitis C virus (HCV) envelope glycoprotein E2 binds to BDCA2 and DCIR, which inhibits IFN-α production in pDC when exposed to HCV-infected hepatocytes (23). Moreover, exposure of pDC to HCV-infected hepatoma cells prevents NF-κB phosphorylation via an endocytosis-dependent mechanism, resulting in a lack of cell surface expression of CD40, CCR7, CD86, and TRAIL, as well as of TNF-α and IL-6 secretion (24). Another example is HIV, which induces production of IFN-α via TLR7 signaling to elicit antiviral activity in acute infection (25). In addition, HIV gp140 binds to DCIR (26) to recruit phosphatases (e.g., SHP1 and SHP2) and tyrosine kinases (e.g., Src, Fyn, Hck, Syk) to the ITIM domain of DCIR (27, 28). Recruitment of this signalosome is important for DCIR activity with regard to HIV binding/entry and enhanced HIV replication (26). It is possible that DCIR activation via gp140 inhibits IFN-α production in pDC, thereby increasing HIV replication. Following HIV-induced IFN-α secretion is expression of IFN-stimulated genes, such as MxA and BST2/Tetherin (29) in surrounding cells. Although increased expression of BST2 on leukocytes, including CD4+ T cells, may play a role in decreasing HIV virion release from infected cells in acute HIV infection (30), BST2 binding to its inhibitory receptor ILT7 expressed on pDC may dampen IFN production (31) and increase viral replication, at least during the acute phase. During chronic HIV infection, sustained levels of IFN-α return, likely as a result of persistent immune activation, leading to HIV pathogenesis. During chronic infection, pDC express increased levels of IRF7 (32) and lower levels of ILT7 (33), which may contribute to persistent IFN-α secretion as well. In addition to IFN-α, TNF-α may be responsible for persistent immune activation, because treatment of SIV-infected rhesus macaques with an Ab to TNF-α reduced expression of proinflammatory cytokines and immunopathology in lymphoid tissues (34).

A new layer of regulation involved in fine-tuning immune responses is provided by microRNAs (35), which are also involved in posttranscriptional regulation of protein expression in pDC. miR-155 and miR-155* have an opposite role in controlling TLR-induced IFN production by human pDC (36). miR-155* augments IFN-α/β expression by suppressing the negative TLR7 signaling mediator IRAKM (37). miR-155 inhibits IFN expression by targeting the adaptor TAK1-binding protein 2 (38). We showed that miR-146a is induced in human pDC by TLR7/9 agonists, but not IL-3, thereby interfering with cytokine production, maturation, and survival (39). Together with similar data in the mouse (34, 40) miR-146a is recognized as a “brake of the immune response” by downregulating IRAK1 and TRAF6 expression and, hence, dampening of TLR-induced responses.

TLR7/9 stimulation of pDC also induces the expression of TRAIL (Apo-2L) (41, 42), which mediates cell death of TRAIL-sensitive infected cells and tumor cells expressing either TRAIL-R1 or TRAIL-R2 (43). Because TRAIL-expressing pDC accumulate in basal cell carcinoma lesions topically treated with the TLR7 agonist imiquimod, this suggests that pDC may be involved in imiquimod-induced regression of tumor lesions (41, 44). In response to HIV, pDC express TRAIL (45), which is present in peripheral blood and lymph nodes of HIV-infected individuals and may directly kill death receptor 5+ CD4+ T cells via the TRAIL/death receptor 5 pathway (46, 47), although this is questioned by other investigators (48). We identified NGFI-A–binding protein 2, which is induced by TLR7/9 signaling in pDC, as a regulator of TRAIL expression (49). Autocrine IFN-α/β signaling also regulates TRAIL expression in human and mouse pDC (41, 4951). pDC may kill target cells via the serine protease granzyme B (GrB) as well, which is constitutively expressed in human pDC (52). pDC-derived GrB lyses the erythroleukemic cell line K562 in a perforin-independent, but caspase-dependent, manner (53). However, this could not be recapitulated when using primary T cells as targets (54).

The ability of pDC to induce adaptive immunity through direct Ag presentation to T cells remained controversial for a long time. Most research focused on cDC, because they are more efficient as APC. Immature mouse pDC are able to take up soluble Ag, but less efficiently than cDC, possibly due to a lower macropinocytosis activity (55). Human pDC express several receptors to detect and endocytose pathogens that can be processed and presented to T cells. Ags coupled to Abs that target the endocytic receptors DEC-205 (56), DCIR (57), FcγRIIa (58), and BDCA2 (59) efficiently induce Ag-specific CD4+ T cell activation. Although BDCA2 (60) and DCIR (57) are downregulated after TLR activation, DEC-205 expression is induced after TLR activation and continues to function as an Ag-internalization receptor (56).

Human pDC can internalize, process, and present Ag via MHC class I and class II to CD8+ and CD4+ T cells, respectively (11, 6163), at least in vitro. Whether pDC act as professional APC in cross-presentation of exogenous Ag has been re-evaluated, and data show that pDC have an efficient machinery allowing cross-presentation to CD8+ T cells (61, 6366). Hence, combined with their capacity to produce IFN-α/β, pDC are interesting targets for immunotherapy.

In the immature state, pDC have a poor ability to support T cell proliferation (67) and even suppress T cell responses indirectly through the induction of regulatory T cells (Treg) (68, 69). pDC contribute to peripheral T cell tolerance in transplantation (70), tumor escape (71), oral tolerance (72), and mucosal tolerance (73). “Tolerogenic” pDC may be present in mouse gut and thymus (7476). Such pDC may express the chemokine receptor CCR9, which is lost upon TLR triggering, correlating with reduced ability to prime tolerance (74). In humans, a similar tolerance-inducing pDC subset has yet to be identified, but pDC expressing either GrB or IDO impair T cell proliferation (54, 71, 77). GrB is induced in pDC by the cytokines IL-21 (54), or IL-3 plus IL-10 (77), and inhibition of GrB activity restored pDC-induced T cell activation (54, 77). IL-21 may be involved in mediating a negative-feedback loop to terminate adaptive-immune responses, because human CD4+ and NK T cells are the main producers in viral or bacterial infections (78).

Melanoma progression in humans may be associated with tumor-infiltrating pDC promoting proinflammatory Th2 and Treg through OX40L and ICOSL, respectively (79), although this conflicts with the observation that patients with metastatic melanoma receiving intranodal injections of pDC mount antitumor responses (80). In addition, a subset of pDC expressing lymphocyte activation gene 3 negatively regulates T cell activation and positively regulates Treg function by production of IL-6 (81, 82). Furthermore, ILT7 on pDC engages BST2 (31), which is endogenously expressed in tumors (reviewed in Ref. 83), thereby suppressing infiltrating pDC to produce IFN in response to TLR ligands and, hence, to induce an antitumor response.

Despite the low frequency of pDC in blood and lymphoid tissues, their high potential to also produce IFN-α in response to self–nucleic acids raised questions about their putative role in autoimmunity. Unwanted IFN-α production by pDC is involved in autoimmune pathogenesis, including systemic lupus erythematosus (SLE) (84, 85), Sjögren’s syndrome (86), and psoriasis (87). Blood and tissue cells of these patients have an IFN signature indicating that IFN-inducible upregulation of IFN-stimulated genes can be used as a disease biomarker (87). In addition to the deleterious effects of IFN, pDC differentiate into mature pDC with an Ag-presenting capacity that is able to steer T cell responses, adding to the pathogenesis of autoimmune diseases.

In SLE, autoantibodies directed to nuclear Ags are aberrantly produced and deposited in tissues, causing inflammation. Nucleic acid–containing immune complexes trigger IFN-α release from pDC upon FcγRIIa-mediated uptake into endosomes and local engagement of TLR7/9 (89, 90). pDC numbers in blood of SLE patients are reduced, but pDC infiltration is found in skin and renal lesions (91). The IFN signature correlates with disease activity and severity (84, 92) but is independent of the relative TLR7 gene copy number (93). SLE pathogenesis can be linked to increased IL-6 production by activated pDC, which, together with IFN-α, promotes survival and differentiation of autoreactive B cells into autoantibody-secreting plasma cells (10). IFN-α production by SLE immune complexes can be inhibited by blocking the FcRγ-mediated uptake of IgG (94) by hydroxychloroquine, which increases the intracytoplasmic pH and prevents acidification and maturation of endosomes (95), or by C-reactive protein, which binds apoptotic cells and nucleoprotein autoantigens (96). Reduced miR-146a expression is found in PBMC of SLE patients and may add to elevated IFN-α and IL-6 levels (97). Accordingly, SLE is associated with miR-146a polymorphisms (98100). Lower expression of miR-146a may be linked to a miR-146a promoter variant binding less efficiently to Ets1 (99). Not all studies support an association between SLE and miR-146 polymorphisms (101). BDCA2 and ILT7, which complex with FcεRIγ, are other negative regulators of TLR-induced IFN-α production in pDC that inhibit SLE pathogenesis (102, 103). This involves a BCR-like signaling mechanism relying on activation of adaptors, such as Syk, B cell linker, and B lymphoid tyrosine kinase (BLK). Reducing BLK levels in mouse pDC increased TLR9-induced IFN-α production (104). Given that genetic variants in the BLK locus are identified in SLE patients by genome-wide association studies, it is notable that certain polymorphisms correlate with reduced BLK levels (105). Consequently, this may increase IFN-α secretion and, hence, contribute to SLE predisposition. SLE patients are generally treated with glucocorticoids (GC) that exert an anti-inflammatory effect, likely by inhibition of NF-κB activation. However, these drugs do not convey maintenance of disease control in the majority of patients as a result of inefficient NF-κB inhibition in pDC (106), thereby preventing GC-induced pDC death and, consequently, ongoing IFN-α production. An improved therapeutic advantage may be gained by treating SLE patients with inhibitors of Syk (107), BTK (108), or TLR (109). Future intervention may aim at altering expression of miR-29b/c, which is involved in TLR-inhibited GC-induced pDC apoptosis, by directly targeting Mcl-1 and Bcl-2 (110).

In psoriasis, a disease of chronic skin inflammation, lesions contain activated pDC that secrete IFN-α/β (87, 111) as a result of the presence of cathelicidin peptides, including LL-37, which are produced by activated keratinocytes (112). LL-37 complexes with self-DNA/RNA released by dying cells and engages TLR7/9, leading to chronic IFN-α production (112, 113). Psoriatic lesions are effectively treated with vitamin D (VitD) analogs, which have anti-inflammatory properties (114). pDC may contribute to the tolerance induction, because VitD impairs the ability of pDC to induce T cell proliferation and secretion of the Th1 cytokine IFN-γ (115). It remains unresolved how VitD programs the tolerogenic properties in pDC, but this is not due to altered expression of costimulatory molecules, MHC class II, or production of IFN-α. Despite the pathological role of pDC in autoimmune skin diseases, the physiological importance of pDC in initiating skin wound healing is also reported. Following skin injury, pDC are rapidly recruited to the site of tissue damage to sense self–nucleic acids released by dying cells in combination with cathelicidins, as well as to initiate tissue repair via TLR-induced IFN-α production (116).

pDC are major inducers of immune responses against viruses and bacteria through TLR7/9 activation. pDC are not only capable of linking the innate and adaptive immune system via rapid and sustained production of cytokines, including type I IFN, IL-6, and TNF-α, they can activate T cells through direct Ag presentation in vitro and, likely, in vivo. In addition, pDC are able to directly kill bystander tumor cells, thereby participating in cancer-induced immune responses. Although the beneficial role of pDC in immunity is undisputable, their recently discovered “tolerogenic” face in different tumors suggests their involvement in tumor-escape mechanisms. Such a broad range of action requires tight regulation, both at the transcriptional and posttranscriptional level, to control development, differentiation, function, and survival of pDC. However, system failures do exist, given the existence of type I IFN–mediated autoimmune diseases. More extensive research on pDC is required to unravel the pathways leading to uncontrolled cytokine production and differentiation to enable therapeutic intervention for curing or stabilizing diseases.

This work was supported by the Dutch Science Foundation Netherlands Organisation for Scientific Research (Grant 917.66.310 to B.B.) and the National Institutes of Health (Grant AI080564 to C.H.U.).

Abbreviations used in this article:

BDCA2

blood DC Ag 2

BLK

B lymphoid tyrosine kinase

cDC

conventional DC

DC

dendritic cell

DCIR

DC immunoreceptor

GC

glucocorticoid

GrB

granzyme B

HCV

hepatitis C virus

ILT7

Ig-like transcript 7

IRAK

IL-1R–associated kinase

IRF

IFN response factor

pDC

plasmacytoid dendritic cell

SLE

systemic erythematosus lupus

Treg

regulatory T cell

VitD

vitamin D.

1
Onai
N.
,
Kurabayashi
K.
,
Hosoi-Amaike
M.
,
Toyama-Sorimachi
N.
,
Matsushima
K.
,
Inaba
K.
,
Ohteki
T.
.
2013
.
A clonogenic progenitor with prominent plasmacytoid dendritic cell developmental potential.
Immunity
38
:
943
957
.
2
Naik
S. H.
,
O’Keeffe
M.
,
Proietto
A.
,
Shortman
H. H.
,
Wu
L.
.
2010
.
CD8+, CD8-, and plasmacytoid dendritic cell generation in vitro using flt3 ligand.
Methods Mol. Biol.
595
:
167
176
.
3
Blom
B.
,
Ho
S.
,
Antonenko
S.
,
Liu
Y. J.
.
2000
.
Generation of interferon alpha-producing predendritic cell (Pre-DC)2 from human CD34(+) hematopoietic stem cells.
J. Exp. Med.
192
:
1785
1796
.
4
Schotte
R.
,
Rissoan
M. C.
,
Bendriss-Vermare
N.
,
Bridon
J. M.
,
Duhen
T.
,
Weijer
K.
,
Brière
F.
,
Spits
H.
.
2003
.
The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development.
Blood
101
:
1015
1023
.
5
Schotte
R.
,
Nagasawa
M.
,
Weijer
K.
,
Spits
H.
,
Blom
B.
.
2004
.
The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development.
J. Exp. Med.
200
:
1503
1509
.
6
Sasaki
I.
,
Hoshino
K.
,
Sugiyama
T.
,
Yamazaki
C.
,
Yano
T.
,
Iizuka
A.
,
Hemmi
H.
,
Tanaka
T.
,
Saito
M.
,
Sugiyama
M.
, et al
.
2012
.
Spi-B is critical for plasmacytoid dendritic cell function and development.
Blood
120
:
4733
4743
.
7
Karrich
J. J.
,
Balzarolo
M.
,
Schmidlin
H.
,
Libouban
M.
,
Nagasawa
M.
,
Gentek
R.
,
Kamihira
S.
,
Maeda
T.
,
Amsen
D.
,
Wolkers
M. C.
,
Blom
B.
.
2012
.
The transcription factor Spi-B regulates human plasmacytoid dendritic cell survival through direct induction of the antiapoptotic gene BCL2-A1.
Blood
119
:
5191
5200
.
8
Cisse
B.
,
Caton
M. L.
,
Lehner
M.
,
Maeda
T.
,
Scheu
S.
,
Locksley
R.
,
Holmberg
D.
,
Zweier
C.
,
den Hollander
N. S.
,
Kant
S. G.
, et al
.
2008
.
Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development.
Cell
135
:
37
48
.
9
Nagasawa
M.
,
Schmidlin
H.
,
Hazekamp
M. G.
,
Schotte
R.
,
Blom
B.
.
2008
.
Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B.
Eur. J. Immunol.
38
:
2389
2400
.
10
Gilliet
M.
,
Lande
R.
.
2008
.
Antimicrobial peptides and self-DNA in autoimmune skin inflammation.
Curr. Opin. Immunol.
20
:
401
407
.
11
Fonteneau
J. F.
,
Gilliet
M.
,
Larsson
M.
,
Dasilva
I.
,
Münz
C.
,
Liu
Y. J.
,
Bhardwaj
N.
.
2003
.
Activation of influenza virus-specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity.
Blood
101
:
3520
3526
.
12
Ito
T.
,
Kanzler
H.
,
Duramad
O.
,
Cao
W.
,
Liu
Y. J.
.
2006
.
Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells.
Blood
107
:
2423
2431
.
13
Yin
Z.
,
Dai
J.
,
Deng
J.
,
Sheikh
F.
,
Natalia
M.
,
Shih
T.
,
Lewis-Antes
A.
,
Amrute
S. B.
,
Garrigues
U.
,
Doyle
S.
, et al
.
2012
.
Type III IFNs are produced by and stimulate human plasmacytoid dendritic cells.
J. Immunol.
189
:
2735
2745
.
14
Bao
M.
,
Liu
Y. J.
.
2013
.
Regulation of TLR7/9 signaling in plasmacytoid dendritic cells.
Protein Cell
4
:
40
52
.
15
Hayden
M. S.
,
West
A. P.
,
Ghosh
S.
.
2006
.
NF-kappaB and the immune response.
Oncogene
25
:
6758
6780
.
16
Hoshino
K.
,
Sugiyama
T.
,
Matsumoto
M.
,
Tanaka
T.
,
Saito
M.
,
Hemmi
H.
,
Ohara
O.
,
Akira
S.
,
Kaisho
T.
.
2006
.
IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9.
Nature
440
:
949
953
.
17
Guiducci
C.
,
Ghirelli
C.
,
Marloie-Provost
M. A.
,
Matray
T.
,
Coffman
R. L.
,
Liu
Y. J.
,
Barrat
F. J.
,
Soumelis
V.
.
2008
.
PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation.
J. Exp. Med.
205
:
315
322
.
18
Shinohara
M. L.
,
Lu
L.
,
Bu
J.
,
Werneck
M. B.
,
Kobayashi
K. S.
,
Glimcher
L. H.
,
Cantor
H.
.
2006
.
Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells.
Nat. Immunol.
7
:
498
506
.
19
Sasai
M.
,
Linehan
M. M.
,
Iwasaki
A.
.
2010
.
Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3.
Science
329
:
1530
1534
.
20
Cao
W.
2009
.
Molecular characterization of human plasmacytoid dendritic cells.
J. Clin. Immunol.
29
:
257
264
.
21
Shin
A.
,
Toy
T.
,
Rothenfusser
S.
,
Robson
N.
,
Vorac
J.
,
Dauer
M.
,
Stuplich
M.
,
Endres
S.
,
Cebon
J.
,
Maraskovsky
E.
,
Schnurr
M.
.
2008
.
P2Y receptor signaling regulates phenotype and IFN-alpha secretion of human plasmacytoid dendritic cells.
Blood
111
:
3062
3069
.
22
Fabricius
D.
,
Neubauer
M.
,
Mandel
B.
,
Schütz
C.
,
Viardot
A.
,
Vollmer
A.
,
Jahrsdörfer
B.
,
Debatin
K. M.
.
2010
.
Prostaglandin E2 inhibits IFN-alpha secretion and Th1 costimulation by human plasmacytoid dendritic cells via E-prostanoid 2 and E-prostanoid 4 receptor engagement.
J. Immunol.
184
:
677
684
.
23
Florentin
J.
,
Aouar
B.
,
Dental
C.
,
Thumann
C.
,
Firaguay
G.
,
Gondois-Rey
F.
,
Soumelis
V.
,
Baumert
T. F.
,
Nunès
J. A.
,
Olive
D.
, et al
.
2012
.
HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells.
Blood
120
:
4544
4551
.
24
Dental
C.
,
Florentin
J.
,
Aouar
B.
,
Gondois-Rey
F.
,
Durantel
D.
,
Baumert
T. F.
,
Nunes
J. A.
,
Olive
D.
,
Hirsch
I.
,
Stranska
R.
.
2012
.
Hepatitis C virus fails to activate NF-κB signaling in plasmacytoid dendritic cells.
J. Virol.
86
:
1090
1096
.
25
Sabado
R. L.
,
O’Brien
M.
,
Subedi
A.
,
Qin
L.
,
Hu
N.
,
Taylor
E.
,
Dibben
O.
,
Stacey
A.
,
Fellay
J.
,
Shianna
K. V.
, et al
.
2010
.
Evidence of dysregulation of dendritic cells in primary HIV infection.
Blood
116
:
3839
3852
.
26
Bloem
K.
,
Vuist
I. M.
,
van den Berk
M.
,
Klaver
E. J.
,
van Die
I.
,
Knippels
L. M.
,
Garssen
J.
,
García-Vallejo
J. J.
,
van Vliet
S. J.
,
van Kooyk
Y.
.
2014
.
DCIR interacts with ligands from both endogenous and pathogenic origin.
Immunol. Lett.
158
:
33
41
.
27
Lambert
A. A.
,
Barabé
F.
,
Gilbert
C.
,
Tremblay
M. J.
.
2011
.
DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway.
Blood
117
:
6589
6599
.
28
Lambert
A. A.
,
Gilbert
C.
,
Richard
M.
,
Beaulieu
A. D.
,
Tremblay
M. J.
.
2008
.
The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways.
Blood
112
:
1299
1307
.
29
Neil
S. J.
,
Zang
T.
,
Bieniasz
P. D.
.
2008
.
Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.
Nature
451
:
425
430
.
30
Homann
S.
,
Smith
D.
,
Little
S.
,
Richman
D.
,
Guatelli
J.
.
2011
.
Upregulation of BST-2/Tetherin by HIV infection in vivo.
J. Virol.
85
:
10659
10668
.
31
Cao
W.
,
Bover
L.
,
Cho
M.
,
Wen
X.
,
Hanabuchi
S.
,
Bao
M.
,
Rosen
D. B.
,
Wang
Y. H.
,
Shaw
J. L.
,
Du
Q.
, et al
.
2009
.
Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction.
J. Exp. Med.
206
:
1603
1614
.
32
O’Brien
M.
,
Manches
O.
,
Sabado
R. L.
,
Baranda
S. J.
,
Wang
Y.
,
Marie
I.
,
Rolnitzky
L.
,
Markowitz
M.
,
Margolis
D. M.
,
Levy
D.
,
Bhardwaj
N.
.
2011
.
Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α-producing and partially matured phenotype.
J. Clin. Invest.
121
:
1088
1101
.
33
Benlahrech
A.
,
Yasmin
A.
,
Westrop
S. J.
,
Coleman
A.
,
Herasimtschuk
A.
,
Page
E.
,
Kelleher
P.
,
Gotch
F.
,
Imami
N.
,
Patterson
S.
.
2012
.
Dysregulated immunophenotypic attributes of plasmacytoid but not myeloid dendritic cells in HIV-1 infected individuals in the absence of highly active anti-retroviral therapy.
Clin. Exp. Immunol.
170
:
212
221
.
34
Boldin
M. P.
,
Taganov
K. D.
,
Rao
D. S.
,
Yang
L.
,
Zhao
J. L.
,
Kalwani
M.
,
Garcia-Flores
Y.
,
Luong
M.
,
Devrekanli
A.
,
Xu
J.
, et al
.
2011
.
miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice.
J. Exp. Med.
208
:
1189
1201
.
35
O’Neill
L. A.
,
Sheedy
F. J.
,
McCoy
C. E.
.
2011
.
MicroRNAs: the fine-tuners of Toll-like receptor signalling.
Nat. Rev. Immunol.
11
:
163
175
.
36
Zhou
H.
,
Huang
X.
,
Cui
H.
,
Luo
X.
,
Tang
Y.
,
Chen
S.
,
Wu
L.
,
Shen
N.
.
2010
.
miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells.
Blood
116
:
5885
5894
.
37
Hassan
F.
,
Islam
S.
,
Tumurkhuu
G.
,
Dagvadorj
J.
,
Naiki
Y.
,
Komatsu
T.
,
Koide
N.
,
Yoshida
T.
,
Yokochi
T.
.
2009
.
Involvement of interleukin-1 receptor-associated kinase (IRAK)-M in toll-like receptor (TLR) 7-mediated tolerance in RAW 264.7 macrophage-like cells.
Cell. Immunol.
256
:
99
103
.
38
Kishida
S.
,
Sanjo
H.
,
Akira
S.
,
Matsumoto
K.
,
Ninomiya-Tsuji
J.
.
2005
.
TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway.
Genes Cells
10
:
447
454
.
39
Karrich
J. J.
,
Jachimowski
L. C.
,
Libouban
M.
,
Iyer
A.
,
Brandwijk
K.
,
Taanman-Kueter
E. W.
,
Nagasawa
M.
,
de Jong
E. C.
,
Uittenbogaart
C. H.
,
Blom
B.
.
2013
.
MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells.
Blood
122
:
3001
3009
.
40
Zhao
J. L.
,
Rao
D. S.
,
Boldin
M. P.
,
Taganov
K. D.
,
O’Connell
R. M.
,
Baltimore
D.
.
2011
.
NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies.
Proc. Natl. Acad. Sci. USA
108
:
9184
9189
.
41
Chaperot
L.
,
Blum
A.
,
Manches
O.
,
Lui
G.
,
Angel
J.
,
Molens
J. P.
,
Plumas
J.
.
2006
.
Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells.
J. Immunol.
176
:
248
255
.
42
Matsui
T.
,
Connolly
J. E.
,
Michnevitz
M.
,
Chaussabel
D.
,
Yu
C.-I.
,
Glaser
C.
,
Tindle
S.
,
Pypaert
M.
,
Freitas
H.
,
Piqueras
B.
, et al
.
2009
.
CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions.
J. Immunol.
182
:
6815
6823
.
43
Blum
A.
,
Chaperot
L.
,
Molens
J.-P.
,
Foissaud
V.
,
Plantaz
D.
,
Plumas
J.
.
2006
.
Mechanisms of TRAIL-induced apoptosis in leukemic plasmacytoid dendritic cells.
Exp. Hematol.
34
:
1655
1662
.
44
Stary
G.
,
Bangert
C.
,
Tauber
M.
,
Strohal
R.
,
Kopp
T.
,
Stingl
G.
.
2007
.
Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells.
J. Exp. Med.
204
:
1441
1451
.
45
Barblu
L.
,
Machmach
K.
,
Gras
C.
,
Delfraissy
J. F.
,
Boufassa
F.
,
Leal
M.
,
Ruiz-Mateos
E.
,
Lambotte
O.
,
Herbeuval
J. P.
ANRS EP36 HIV Controllers Study Group
.
2012
.
Plasmacytoid dendritic cells (pDCs) from HIV controllers produce interferon-α and differentiate into functional killer pDCs under HIV activation.
J. Infect. Dis.
206
:
790
801
.
46
Stary
G.
,
Klein
I.
,
Kohlhofer
S.
,
Koszik
F.
,
Scherzer
T.
,
Müllauer
L.
,
Quendler
H.
,
Kohrgruber
N.
,
Stingl
G.
.
2009
.
Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients.
Blood
114
:
3854
3863
.
47
Hardy
A. W.
,
Graham
D. R.
,
Shearer
G. M.
,
Herbeuval
J.-P.
.
2007
.
HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha.
Proc. Natl. Acad. Sci. USA
104
:
17453
17458
.
48
Chehimi
J.
,
Papasavvas
E.
,
Tomescu
C.
,
Gekonge
B.
,
Abdulhaqq
S.
,
Raymond
A.
,
Hancock
A.
,
Vinekar
K.
,
Carty
C.
,
Reynolds
G.
, et al
.
2010
.
Inability of plasmacytoid dendritic cells to directly lyse HIV-infected autologous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligand.
J. Virol.
84
:
2762
2773
.
49
Balzarolo
M.
,
Karrich
J. J.
,
Engels
S.
,
Blom
B.
,
Medema
J. P.
,
Wolkers
M. C.
.
2012
.
The transcriptional regulator NAB2 reveals a two-step induction of TRAIL in activated plasmacytoid DCs.
Eur. J. Immunol.
42
:
3019
3027
.
50
Drobits
B.
,
Holcmann
M.
,
Amberg
N.
,
Swiecki
M.
,
Grundtner
R.
,
Hammer
M.
,
Colonna
M.
,
Sibilia
M.
.
2012
.
Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells.
J. Clin. Invest.
122
:
575
585
.
51
Kalb
M. L.
,
Glaser
A.
,
Stary
G.
,
Koszik
F.
,
Stingl
G.
.
2012
.
TRAIL(+) human plasmacytoid dendritic cells kill tumor cells in vitro: mechanisms of imiquimod- and IFN-α-mediated antitumor reactivity.
J. Immunol.
188
:
1583
1591
.
52
Rissoan
M. C.
,
Duhen
T.
,
Bridon
J. M.
,
Bendriss-Vermare
N.
,
Péronne
C.
,
de Saint Vis
B.
,
Brière
F.
,
Bates
E. E.
.
2002
.
Subtractive hybridization reveals the expression of immunoglobulin-like transcript 7, Eph-B1, granzyme B, and 3 novel transcripts in human plasmacytoid dendritic cells.
Blood
100
:
3295
3303
.
53
Bratke
K.
,
Nielsen
J.
,
Manig
F.
,
Klein
C.
,
Kuepper
M.
,
Geyer
S.
,
Julius
P.
,
Lommatzsch
M.
,
Virchow
J. C.
.
2010
.
Functional expression of granzyme B in human plasmacytoid dendritic cells: a role in allergic inflammation.
Clin. Exp. Allergy
40
:
1015
1024
.
54
Karrich
J. J.
,
Jachimowski
L. C.
,
Nagasawa
M.
,
Kamp
A.
,
Balzarolo
M.
,
Wolkers
M. C.
,
Uittenbogaart
C. H.
,
Marieke van Ham
S.
,
Blom
B.
.
2013
.
IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation.
Blood
121
:
3103
3111
.
55
Young
L. J.
,
Wilson
N. S.
,
Schnorrer
P.
,
Proietto
A.
,
ten Broeke
T.
,
Matsuki
Y.
,
Mount
A. M.
,
Belz
G. T.
,
O’Keeffe
M.
,
Ohmura-Hoshino
M.
, et al
.
2008
.
Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells.
Nat. Immunol.
9
:
1244
1252
.
56
Tel
J.
,
Benitez-Ribas
D.
,
Hoosemans
S.
,
Cambi
A.
,
Adema
G. J.
,
Figdor
C. G.
,
Tacken
P. J.
,
de Vries
I. J.
.
2011
.
DEC-205 mediates antigen uptake and presentation by both resting and activated human plasmacytoid dendritic cells.
Eur. J. Immunol.
41
:
1014
1023
.
57
Meyer-Wentrup
F.
,
Benitez-Ribas
D.
,
Tacken
P. J.
,
Punt
C. J.
,
Figdor
C. G.
,
de Vries
I. J.
,
Adema
G. J.
.
2008
.
Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-alpha production.
Blood
111
:
4245
4253
.
58
Benitez-Ribas
D.
,
Tacken
P.
,
Punt
C. J.
,
de Vries
I. J.
,
Figdor
C. G.
.
2008
.
Activation of human plasmacytoid dendritic cells by TLR9 impairs Fc gammaRII-mediated uptake of immune complexes and presentation by MHC class II.
J. Immunol.
181
:
5219
5224
.
59
Dzionek
A.
,
Sohma
Y.
,
Nagafune
J.
,
Cella
M.
,
Colonna
M.
,
Facchetti
F.
,
Günther
G.
,
Johnston
I.
,
Lanzavecchia
A.
,
Nagasaka
T.
, et al
.
2001
.
BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction.
J. Exp. Med.
194
:
1823
1834
.
60
Wu
P.
,
Wu
J.
,
Liu
S.
,
Han
X.
,
Lu
J.
,
Shi
Y.
,
Wang
J.
,
Lu
L.
,
Cao
X.
.
2008
.
TLR9/TLR7-triggered downregulation of BDCA2 expression on human plasmacytoid dendritic cells from healthy individuals and lupus patients.
Clin. Immunol.
129
:
40
48
.
61
Di Pucchio
T.
,
Chatterjee
B.
,
Smed-Sörensen
A.
,
Clayton
S.
,
Palazzo
A.
,
Montes
M.
,
Xue
Y.
,
Mellman
I.
,
Banchereau
J.
,
Connolly
J. E.
.
2008
.
Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I.
Nat. Immunol.
9
:
551
557
.
62
Guillerme
J. B.
,
Boisgerault
N.
,
Roulois
D.
,
Ménager
J.
,
Combredet
C.
,
Tangy
F.
,
Fonteneau
J. F.
,
Gregoire
M.
.
2013
.
Measles virus vaccine-infected tumor cells induce tumor antigen cross-presentation by human plasmacytoid dendritic cells.
Clin. Cancer Res.
19
:
1147
1158
.
63
Tel
J.
,
Schreibelt
G.
,
Sittig
S. P.
,
Mathan
T. S.
,
Buschow
S. I.
,
Cruz
L. J.
,
Lambeck
A. J.
,
Figdor
C. G.
,
de Vries
I. J.
.
2013
.
Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets.
Blood
121
:
459
467
.
64
Hoeffel
G.
,
Ripoche
A. C.
,
Matheoud
D.
,
Nascimbeni
M.
,
Escriou
N.
,
Lebon
P.
,
Heshmati
F.
,
Guillet
J. G.
,
Gannagé
M.
,
Caillat-Zucman
S.
, et al
.
2007
.
Antigen crosspresentation by human plasmacytoid dendritic cells.
Immunity
27
:
481
492
.
65
Lui
G.
,
Manches
O.
,
Angel
J.
,
Molens
J. P.
,
Chaperot
L.
,
Plumas
J.
.
2009
.
Plasmacytoid dendritic cells capture and cross-present viral antigens from influenza-virus exposed cells.
PLoS ONE
4
:
e7111
.
66
Tel
J.
,
Sittig
S. P.
,
Blom
R. A.
,
Cruz
L. J.
,
Schreibelt
G.
,
Figdor
C. G.
,
de Vries
I. J.
.
2013
.
Targeting uptake receptors on human plasmacytoid dendritic cells triggers antigen cross-presentation and robust type I IFN secretion.
J. Immunol.
191
:
5005
5012
.
67
Asselin-Paturel
C.
,
Boonstra
A.
,
Dalod
M.
,
Durand
I.
,
Yessaad
N.
,
Dezutter-Dambuyant
C.
,
Vicari
A.
,
O’Garra
A.
,
Biron
C.
,
Brière
F.
,
Trinchieri
G.
.
2001
.
Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology.
Nat. Immunol.
2
:
1144
1150
.
68
Hanabuchi
S.
,
Ito
T.
,
Park
W. R.
,
Watanabe
N.
,
Shaw
J. L.
,
Roman
E.
,
Arima
K.
,
Wang
Y. H.
,
Voo
K. S.
,
Cao
W.
,
Liu
Y. J.
.
2010
.
Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus.
J. Immunol.
184
:
2999
3007
.
69
Martín-Gayo
E.
,
Sierra-Filardi
E.
,
Corbí
A. L.
,
Toribio
M. L.
.
2010
.
Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development.
Blood
115
:
5366
5375
.
70
Ochando
J. C.
,
Homma
C.
,
Yang
Y.
,
Hidalgo
A.
,
Garin
A.
,
Tacke
F.
,
Angeli
V.
,
Li
Y.
,
Boros
P.
,
Ding
Y.
, et al
.
2006
.
Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts.
Nat. Immunol.
7
:
652
662
.
71
Munn
D. H.
,
Sharma
M. D.
,
Hou
D.
,
Baban
B.
,
Lee
J. R.
,
Antonia
S. J.
,
Messina
J. L.
,
Chandler
P.
,
Koni
P. A.
,
Mellor
A. L.
.
2004
.
Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes.
J. Clin. Invest.
114
:
280
290
.
72
Goubier
A.
,
Dubois
B.
,
Gheit
H.
,
Joubert
G.
,
Villard-Truc
F.
,
Asselin-Paturel
C.
,
Trinchieri
G.
,
Kaiserlian
D.
.
2008
.
Plasmacytoid dendritic cells mediate oral tolerance.
Immunity
29
:
464
475
.
73
de Heer
H. J.
,
Hammad
H.
,
Soullié
T.
,
Hijdra
D.
,
Vos
N.
,
Willart
M. A.
,
Hoogsteden
H. C.
,
Lambrecht
B. N.
.
2004
.
Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.
J. Exp. Med.
200
:
89
98
.
74
Hadeiba
H.
,
Lahl
K.
,
Edalati
A.
,
Oderup
C.
,
Habtezion
A.
,
Pachynski
R.
,
Nguyen
L.
,
Ghodsi
A.
,
Adler
S.
,
Butcher
E. C.
.
2012
.
Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance.
Immunity
36
:
438
450
.
75
Hadeiba
H.
,
Sato
T.
,
Habtezion
A.
,
Oderup
C.
,
Pan
J.
,
Butcher
E. C.
.
2008
.
CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease.
Nat. Immunol.
9
:
1253
1260
.
76
Mizuno, S., T. Kanai, Y. Mikami, T. Sujino, Y. Ono, A. Hayashi, T. Handa, A. Matsumoto, N. Nakamoto, K. Matsuoka, et al. 2012. CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice. Immunol Lett. 146: 64–69.
77
Jahrsdörfer
B.
,
Vollmer
A.
,
Blackwell
S. E.
,
Maier
J.
,
Sontheimer
K.
,
Beyer
T.
,
Mandel
B.
,
Lunov
O.
,
Tron
K.
,
Nienhaus
G. U.
, et al
.
2010
.
Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion.
Blood
115
:
1156
1165
.
78
Parrish-Novak
J.
,
Dillon
S. R.
,
Nelson
A.
,
Hammond
A.
,
Sprecher
C.
,
Gross
J. A.
,
Johnston
J.
,
Madden
K.
,
Xu
W.
,
West
J.
, et al
.
2000
.
Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.
Nature
408
:
57
63
.
79
Aspord
C.
,
Leccia
M. T.
,
Charles
J.
,
Plumas
J.
.
2013
.
Plasmacytoid dendritic cells support melanoma progression by promoting Th2 and regulatory immunity through OX40L and ICOSL.
Cancer Immunol. Res.
1
:
402
415
.
80
Tel
J.
,
Aarntzen
E. H.
,
Baba
T.
,
Schreibelt
G.
,
Schulte
B. M.
,
Benitez-Ribas
D.
,
Boerman
O. C.
,
Croockewit
S.
,
Oyen
W. J.
,
van Rossum
M.
, et al
.
2013
.
Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients.
Cancer Res.
73
:
1063
1075
.
81
Camisaschi, C., A. De Filippo, V. Beretta, B. Vergani, A. Villa, E. Vergani, M. Santinami, A. D. Cabras, F. Arienti, F. Triebel, et al. 2014. Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J. Invest. Dermatol. 134: 1893–1902.
82
Workman
C. J.
,
Wang
Y.
,
El Kasmi
K. C.
,
Pardoll
D. M.
,
Murray
P. J.
,
Drake
C. G.
,
Vignali
D. A.
.
2009
.
LAG-3 regulates plasmacytoid dendritic cell homeostasis.
J. Immunol.
182
:
1885
1891
.
83
Cao
W.
,
Bover
L.
.
2010
.
Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells.
Immunol. Rev.
234
:
163
176
.
84
Baechler
E. C.
,
Batliwalla
F. M.
,
Karypis
G.
,
Gaffney
P. M.
,
Ortmann
W. A.
,
Espe
K. J.
,
Shark
K. B.
,
Grande
W. J.
,
Hughes
K. M.
,
Kapur
V.
, et al
.
2003
.
Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.
Proc. Natl. Acad. Sci. USA
100
:
2610
2615
.
85
Bennett
L.
,
Palucka
A. K.
,
Arce
E.
,
Cantrell
V.
,
Borvak
J.
,
Banchereau
J.
,
Pascual
V.
.
2003
.
Interferon and granulopoiesis signatures in systemic lupus erythematosus blood.
J. Exp. Med.
197
:
711
723
.
86
Gottenberg
J. E.
,
Cagnard
N.
,
Lucchesi
C.
,
Letourneur
F.
,
Mistou
S.
,
Lazure
T.
,
Jacques
S.
,
Ba
N.
,
Ittah
M.
,
Lepajolec
C.
, et al
.
2006
.
Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome.
Proc. Natl. Acad. Sci. USA
103
:
2770
2775
.
87
Nestle
F. O.
,
Conrad
C.
,
Tun-Kyi
A.
,
Homey
B.
,
Gombert
M.
,
Boyman
O.
,
Burg
G.
,
Liu
Y. J.
,
Gilliet
M.
.
2005
.
Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.
J. Exp. Med.
202
:
135
143
.
88
Higgs
B. W.
,
Liu
Z.
,
White
B.
,
Zhu
W.
,
White
W. I.
,
Morehouse
C.
,
Brohawn
P.
,
Kiener
P. A.
,
Richman
L.
,
Fiorentino
D.
, et al
.
2011
.
Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway.
Ann. Rheum. Dis.
70
:
2029
2036
.
89
Crow
M. K.
2014
.
Type I interferon in the pathogenesis of lupus.
J. Immunol.
192
:
5459
5468
.
90
Lövgren
T.
,
Eloranta
M. L.
,
Båve
U.
,
Alm
G. V.
,
Rönnblom
L.
.
2004
.
Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG.
Arthritis Rheum.
50
:
1861
1872
.
91
Farkas
L.
,
Beiske
K.
,
Lund-Johansen
F.
,
Brandtzaeg
P.
,
Jahnsen
F. L.
.
2001
.
Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions.
Am. J. Pathol.
159
:
237
243
.
92
Bengtsson
A. A.
,
Sturfelt
G.
,
Truedsson
L.
,
Blomberg
J.
,
Alm
G.
,
Vallin
H.
,
Rönnblom
L.
.
2000
.
Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies.
Lupus
9
:
664
671
.
93
Kelley
J.
,
Johnson
M. R.
,
Alarcón
G. S.
,
Kimberly
R. P.
,
Edberg
J. C.
.
2007
.
Variation in the relative copy number of the TLR7 gene in patients with systemic lupus erythematosus and healthy control subjects.
Arthritis Rheum.
56
:
3375
3378
.
94
Wiedeman
A. E.
,
Santer
D. M.
,
Yan
W.
,
Miescher
S.
,
Käsermann
F.
,
Elkon
K. B.
.
2013
.
Contrasting mechanisms of interferon-α inhibition by intravenous immunoglobulin after induction by immune complexes versus Toll-like receptor agonists.
Arthritis Rheum.
65
:
2713
2723
.
95
Sacre
K.
,
Criswell
L. A.
,
McCune
J. M.
.
2012
.
Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus.
Arthritis Res. Ther.
14
:
R155
.
96
Mold
C.
,
Clos
T. W.
.
2013
.
C-reactive protein inhibits plasmacytoid dendritic cell interferon responses to autoantibody immune complexes.
Arthritis Rheum.
65
:
1891
1901
.
97
Tang
Y.
,
Luo
X.
,
Cui
H.
,
Ni
X.
,
Yuan
M.
,
Guo
Y.
,
Huang
X.
,
Zhou
H.
,
de Vries
N.
,
Tak
P. P.
, et al
.
2009
.
MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins.
Arthritis Rheum.
60
:
1065
1075
.
98
Zhang
J.
,
Yang
B.
,
Ying
B.
,
Li
D.
,
Shi
Y.
,
Song
X.
,
Cai
B.
,
Huang
Z.
,
Wu
Y.
,
Wang
L.
.
2011
.
Association of pre-microRNAs genetic variants with susceptibility in systemic lupus erythematosus.
Mol. Biol. Rep.
38
:
1463
1468
.
99
Luo
X.
,
Yang
W.
,
Ye
D. Q.
,
Cui
H.
,
Zhang
Y.
,
Hirankarn
N.
,
Qian
X.
,
Tang
Y.
,
Lau
Y. L.
,
de Vries
N.
, et al
.
2011
.
A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus.
PLoS Genet.
7
:
e1002128
.
100
Löfgren
S. E.
,
Frostegård
J.
,
Truedsson
L.
,
Pons-Estel
B. A.
,
D’Alfonso
S.
,
Witte
T.
,
Lauwerys
B. R.
,
Endreffy
E.
,
Kovács
L.
,
Vasconcelos
C.
, et al
.
2012
.
Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene.
Genes Immun.
13
:
268
274
.
101
Jiménez-Morales
S.
,
Gamboa-Becerra
R.
,
Baca
V.
,
Del Río-Navarro
B. E.
,
López-Ley
D. Y.
,
Velázquez-Cruz
R.
,
Saldaña-Alvarez
Y.
,
Salas-Martínez
G.
,
Orozco
L.
.
2012
.
MiR-146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients.
Tissue Antigens
80
:
317
321
.
102
Cao
W.
,
Zhang
L.
,
Rosen
D. B.
,
Bover
L.
,
Watanabe
G.
,
Bao
M.
,
Lanier
L. L.
,
Liu
Y. J.
.
2007
.
BDCA2/Fc epsilon RI gamma complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells.
PLoS Biol.
5
:
e248
.
103
Cao
W.
,
Rosen
D. B.
,
Ito
T.
,
Bover
L.
,
Bao
M.
,
Watanabe
G.
,
Yao
Z.
,
Zhang
L.
,
Lanier
L. L.
,
Liu
Y. J.
.
2006
.
Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production.
J. Exp. Med.
203
:
1399
1405
.
104
Samuelson
E. M.
,
Laird
R. M.
,
Papillion
A. M.
,
Tatum
A. H.
,
Princiotta
M. F.
,
Hayes
S. M.
.
2014
.
Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice.
PLoS ONE
9
:
e92054
.
105
Delgado-Vega
A. M.
,
Dozmorov
M. G.
,
Quirós
M. B.
,
Wu
Y. Y.
,
Martínez-García
B.
,
Kozyrev
S. V.
,
Frostegård
J.
,
Truedsson
L.
,
de Ramón
E.
,
González-Escribano
M. F.
, et al
.
2012
.
Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein.
Ann. Rheum. Dis.
71
:
1219
1226
.
106
Guiducci
C.
,
Gong
M.
,
Xu
Z.
,
Gill
M.
,
Chaussabel
D.
,
Meeker
T.
,
Chan
J. H.
,
Wright
T.
,
Punaro
M.
,
Bolland
S.
, et al
.
2010
.
TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus.
Nature
465
:
937
941
.
107
Liao
C.
,
Hsu
J.
,
Kim
Y.
,
Hu
D. Q.
,
Xu
D.
,
Zhang
J.
,
Pashine
A.
,
Menke
J.
,
Whittard
T.
,
Romero
N.
, et al
.
2013
.
Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy.
Arthritis Res. Ther.
15
:
R146
.
108
Wang
J.
,
Lau
K. Y.
,
Jung
J.
,
Ravindran
P.
,
Barrat
F. J.
.
2014
.
Bruton’s tyrosine kinase regulates TLR9 but not TLR7 signaling in human plasmacytoid dendritic cells.
Eur. J. Immunol.
44
:
1130
1136
.
109
Barrat
F. J.
,
Coffman
R. L.
.
2008
.
Development of TLR inhibitors for the treatment of autoimmune diseases.
Immunol. Rev.
223
:
271
283
.
110
Hong
Y.
,
Wu
J.
,
Zhao
J.
,
Wang
H.
,
Liu
Y.
,
Chen
T.
,
Kan
X.
,
Tao
Q.
,
Shen
X.
,
Yan
K.
,
Zhai
Z.
.
2013
.
miR-29b and miR-29c are involved in Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid dendritic cells.
PLoS ONE
8
:
e69926
.
111
Albanesi
C.
,
Scarponi
C.
,
Pallotta
S.
,
Daniele
R.
,
Bosisio
D.
,
Madonna
S.
,
Fortugno
P.
,
Gonzalvo-Feo
S.
,
Franssen
J. D.
,
Parmentier
M.
, et al
.
2009
.
Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment.
J. Exp. Med.
206
:
249
258
.
112
Lande
R.
,
Gregorio
J.
,
Facchinetti
V.
,
Chatterjee
B.
,
Wang
Y. H.
,
Homey
B.
,
Cao
W.
,
Wang
Y. H.
,
Su
B.
,
Nestle
F. O.
, et al
.
2007
.
Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.
Nature
449
:
564
569
.
113
Ganguly
D.
,
Chamilos
G.
,
Lande
R.
,
Gregorio
J.
,
Meller
S.
,
Facchinetti
V.
,
Homey
B.
,
Barrat
F. J.
,
Zal
T.
,
Gilliet
M.
.
2009
.
Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.
J. Exp. Med.
206
:
1983
1994
.
114
Kragballe
K.
1995
.
Calcipotriol: a new drug for topical psoriasis treatment.
Pharmacol. Toxicol.
77
:
241
246
.
115
Karthaus
N.
,
van Spriel
A. B.
,
Looman
M. W.
,
Chen
S.
,
Spilgies
L. M.
,
Lieben
L.
,
Carmeliet
G.
,
Ansems
M.
,
Adema
G. J.
.
2014
.
Vitamin D controls murine and human plasmacytoid dendritic cell function.
J. Invest. Dermatol.
134
:
1255
1264
.
116
Gregorio
J.
,
Meller
S.
,
Conrad
C.
,
Di Nardo
A.
,
Homey
B.
,
Lauerma
A.
,
Arai
N.
,
Gallo
R. L.
,
Digiovanni
J.
,
Gilliet
M.
.
2010
.
Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons.
J. Exp. Med.
207
:
2921
2930
.

The authors have no financial conflicts of interest.