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. Author manuscript; available in PMC: 2014 Jun 1.
Published in final edited form as: Allergy. 2013 May 11;68(6):695–701. doi: 10.1111/all.12166

Role of plasmacytoid dendritic cell subsets in allergic asthma

Hadi Maazi 1, Jonathan Lam 1, Vincent Lombardi 1, Omid Akbari 1
PMCID: PMC3693732  NIHMSID: NIHMS471916  PMID: 23662841

Abstract

Plasmacytoid dendritic cells (pDCs) are major type-I interferon producing cells that play important roles in antiviral immunity and tolerance induction. These cells share a common DC progenitor with conventional DCs and Fms-like tyrosine kinase-3 ligand is essential for their development. Several subsets of pDCs have been identified to date including CCR9+, CD9+ and CD2+ pDCs. Recently, three subsets of pDCs were described namely, CD8α−β−, CD8α+β− and CD8α+β+ subsets. Interestingly, CD8α+β− and CD8α+β+ but not CD8α−β− pDCs were shown to have tolerogenic effects in experimentally induced allergic asthma. These tolerogenic effects were shown to be mediated by the generation of FOXP3+ regulatory T cells through retinoic acid and the induction of retinaldehyde dehydrogenase enzymes. These newly described subsets of pDCs show high potentials for novel therapeutic approaches for the treatment of allergic diseases. In this review, we will address the new progress in our understanding of pDC biology with respect to allergic disease in particular allergic asthma.

Keywords: plasmacytoid dendritic cells, allergy, tolerance, pDCs, Allergic asthma

Introduction

Plasmacytoid dendritic cells (pDCs) are the major type-I interferon producing cells that are implicated in antiviral immunity and immunological tolerance 1–6. Since their first discovery in 1958 there has been a substantial improvement in our understanding of these cells 7. In the steady state, pDCs show plasma cell like morphology and express CD11c, CD45R, PDCA-1, Siglec-H, but not CD11b in mice, and CD4, CD45RA, CD303 and CD123 but not CD11c in humans 1, 8–10. Under inflammatory conditions and upon activation, pDCs show a classical DC morphology with dendrites 11. These cells sense pathogens through Toll-like receptor-7 and 9 leading to their rapid and robust secretion of type-I interferons (IFNs) 12, 13. This unique capacity of pDCs to secrete high levels of IFN-α is crucial in innate anti-viral immunity 14–16.

In adaptive immunity, pDCs play major roles in the induction of immunological tolerance. Unlike conventional DCs, pDCs are poor antigen presenting cells to CD4+ T cells mainly due to their less-efficient antigen processing machinery and low expression of co-stimulatory molecules 1, 11, 17. However, there is evidence suggesting that pDCs can efficiently present antigens to CD8+ T cells 18. pDCs contribute to the induction of tolerance through enhancing the generation of regulatory T (Treg) cells 19–26. It has been shown that a subset of Thymic Stromal Lymphopoietin Protein receptor expressing human pDCs potentiates the generation of naturally occurring T cells in the thymus 27. There is also evidence indicating that pDCs contribute to the induction of Treg cells required for immune tolerance in allergic and autoimmune diseases, cancer, transplant and fetal tolerance 19–26.

pDC ontogeny

Understanding the pDC ontogeny and pDC progenitors is an interesting issue that has attracted the attention of many research groups. It has been shown in human and mouse that hematopoietic stem cells (HSC) can ultimately give rise to pDCs and conventional DCs in the bone marrow 28. HSCs can differentiate to either common lymphoid progenitor (CLPs) or common myeloid progenitors (CMPs) 29 and it has been well established that both CMPs and CLPs can give rise to pDCs or cDCs 28, 30, 31. It was found that a subpopulation of pDCs transiently expresses recombination activating gene-1 (RAG-1) during development and it was thought that only CLP-derived pDCs had expressed RAG-1 32, 33. However, it was recently reported that all CLP-derived pDCs and a subpopulation of CMP-derived pDCs had expressed RAG-1 during their development and in this respect show similarity to B cells 34.

Monocyte DC progenitors (MDPs) are further differentiated progenitors for both pDCs and cDCs that originate from CMPs 35, 36. Fms-like tyrosine kinase 3 ligand (Flt3-L) is an essential cytokine in DC development and its receptor Flt3 is broadly expressed by DC progenitors in bone marrow 37, 38. Flt3-L drives the differentiation of common DC Progenitors from MDPs and further to either pDCs or pre-DCs 39.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is another important factor in DC development that was initially identified as a requirement for in vitro generation of DCs 40. However, the development of DCs is only partially ablated in the absence of GM-CSF or its receptor in mice 41. It was thought that Flt3-L mediated generation of DCs resembles the generation of DCs in vivo in steady state42, whereas GM-CSF mainly drives inflammatory DCs 43. Nevertheless, a recent report from Merad group suggests that GM-CSF is dispensable for the generation of inflammatory DCs 44.

PDCs in allergic diseases

Several lines of research have shown a role for tolerogenic pDCs in allergic diseases including allergic asthma. In a clinical study, it was found that the number of pDCs in infancy inversely correlates with asthma development during the first five years of life 45. A recent study shows that human tonsilar pDCs have the capability to induce functional FOXP3+ Treg cells that can suppress effector T cells in vitro 46. This study reports that pDCs co-localize with FOXP3+ Treg cells in human tonsils in vivo 46.

In mice, depletion of pDCs has been shown to cause sensitization and lung inflammation to a harmless antigen 47. Increased number of pDCs due to administration of Flt-3L has been reported to be associated with alleviated asthma-like symptoms in mice, which is reversed after depletion of pDCs 48. Besides allergic asthma, there is evidence suggesting that pDCs play tolerogenic roles in food allergy 49. Flt3-L-mediated expansion of pDCs has been shown to inhibit the development of allergic inflammation in the intestines in a murine model of food allergy 49. Altogether, these studies indicate an important role for pDCs in fine tuned regulation of immunological tolerance in allergic asthma.

Regulation of tolerance

The tolerogenic role of pDCs is delicately tuned to the circumstances of antigen exposure and whether pathogen associated molecular patterns are present 50–52. Under steady state, pDCs play a tolerogenic role in allergic asthma; however, this effect is abrogated in the presence of danger signals and infectious agents. Adoptive transfer of pDCs from sensitized donors to sensitized recipient has been shown to inhibit the development of house dust mite-driven allergic asthma in a mouse model 53. This effect was abrogated when the transferred pDCs were infected by respiratory syncytial virus (RSV) 53. Interestingly, it has been reported that ex vivo RSV-infected human pDCs express higher levels of T cell co-stimulatory molecule, CD86 and pro-inflammatory cytokine IL-8, suggesting that pDCs play a role in eliciting the immune response rather than tolerance in the presence of RSV 50. Another study has shown that while low dose infection with Chlamydia pneumoniae facilitates sensitization and development of allergic asthma, high dose C.pneumoniae infection increases the number of pDCs and Treg cells in the lungs and prevents allergic sensitization in a mouse model 54. Unlike infectious agents, the presence of innocuous gut flora seems to be important for induction of pDC mediated allergen tolerance. Germ free mice have reduced number of pDCs and macrophages in their lungs and show exacerbated airway eosinophilia, IgE production and Th2 cells compare to specified pathogen free mice 55. In humans, Bifidobacterium infantis feeding was shown to induce peripheral FOXP3+ Treg cells as well as induction of IDO in pDCs through TLR-9 stimulation in vitro, which suggests a role for IDO expressing pDCs in the induction of oral tolerance by microbiota 51. Recently, it was shown that Siglec-H that is exclusively expressed by pDCs and recognizes sialic acid molecules of pathogens, is required for eliciting CD8 mediated immune response as well as for the generation of inducible FOXP3+ Treg cells in vivo 52. Taken together, evidence suggests that pDCs fine-tune the balance between immune response and tolerance based on the presence or absence of danger signals that stimulate pattern recognition receptors on these cells.

PDC subsets

Based on the expression of cell surface markers, pDCs have been further categorized into different subsets (Table 1). Expression of CCR9 on mouse pDCs was first reported by Wendland and colleagues as an intestine homing receptor 56. Subsequently, Hadeiba and colleagues found that CCR9 expressing pDCs suppress acute graft-versus-host disease in mice 57. Whether the CCR9+ pDCs have a human counterpart and can contribute to maintaining tolerance to allergens remains to be elucidated. It has been recently shown that in the steady state, CCR9+ pDCs are terminally differentiated subsets present only in the liver and bone marrow but not in the lungs 58, ruling out that CCR9+ pDCs might play a role in allergic asthma.

Table 1.

Function of pDC subsets involved in the pathology of various diseases.

pDC subsets Function Tissue Species Reference
CCR9 CCR9+ Associated with suppressing acute graft host disease and ulcerative colitis by inducing Treg cells and suppressing antigen-specific immune responses. Intesti, bone marro, liver, lung Mouse 52–54
CCR9− Acts as a precursor for CCR9+ pDC or conventional DC depending on the tissue.
CD9Siglec-H CD9+Siglc-H(low) Secretes high levels of IFN-α upon TLR stimulation, induces cytotoxic T lymphocytes and promote antitumor activity. Bone marro, Liver Mouse 55
CD9−Siglec-H(high) Secretes negligible IFN-α levels, induces Foxp3+ Treg cells and fails to promote antitumor immunity. Involved in hepatitis C virus recognition after infection.
CD8αβ CD8α+β+ CD8a+β− Activates FoxP3+ Treg cells to induce tolerance by increasing retinoic acid production. Lung Mouse 57
CD8α−β−/− Activates Teff cells to induce airway inflammation and airway hyperreactivity.
CD2 CD2(high) Produces IFN-α, granzyme B, TRAIL, lysozyme and can recall T cell responses. Also produces higher levels of IL-12p40, CD80 and more efficiently triggers proliferation of naοve allogeneic T cell than CD2(low). Tonsils and tumors Human 56
CD2(low) CD2(low) pDC are depleted in HIV subjects.
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Recently, the Engleman group reported that mouse CD9+ and CD9− pDCs have distinct roles in anti tumor immunity and tolerance 59. They reported that CD9+ Siglec-Hlow pDCs secrete high level of IFN-α when stimulated with Toll Like Receptor (TLR) agonists and promote anti tumor immunity. In contrast, CD9− Siglec-Hhi pDCs were found to secrete low amounts of IFN-α and induce FOXP3+ CD4 T cells 59. Nonetheless, it is unknown whether there is a human counterpart for CD9+ pDC subsets and whether these cells migrate to the lungs to play a role in the immune regulation in this organ.

It has been reported that CD2hi human pDCs obtained from buffy coat packs secrete higher levels of Interleukin (IL)-12p40, show higher expression of costimulatory molecule CD80 and higher capacity in priming allogenic T cells 60. However, it is not currently known, whether CD2hi pDCs posses any crucial capacity in the induction of tolerance in allergic diseases.

Newly described CD8α+ pDC subsets in allergic asthma

Recently, three new subsets of pDCs have been described based on the expression of CD8α and β chain, which include CD8α−β− , CD8α+β− and CD8α+β+ 61. The frequency of these cells is reported to be 61%, 22% and 6% in the lungs of naïve mice respectively. Besides lungs, these three subsets are also present in peripheral lymph nodes and spleen 61. In the steady state, the three subsets express equal levels of Siglec-H, Ly6c, B220, Ly49Q, Programmed cell death ligand-1 (PD-L1), Programmed cell death ligand-2 (PD-L2) and Inducible costimulator-ligand 61 . Interestingly, it is found that only CD8α+β− and CD8α+β+ subsets have the tolerogenic capacities in allergic asthma and CD8α−β− pDCs lack this capacity. In fact, CD8α−β− pDCs produce substantially higher levels of IFN-α, IL-6, Tumor Necrosis Factor (TNF)-α and IL-10 compared to CD8α+β− and CD8α+β+ subsets upon stimulation with TLR-7 or TLR-9 agonists 61. Furthermore, CD8α−β− pDCs are more efficient in antigen uptake and in priming naïve CD4+ T cells in vitro than the other two subsets as evident by higher naïve CD4+ T cell proliferation and IL-2 production in pDC T cell co-culture in the presence of antigen 61.

In vivo, when the three subsets are loaded with ovalbumin (OVA) and transferred to naïve mice, only CD8α−β− pDCs can prime T cells, sensitize the mice and lead to the induction of asthma-like symptoms upon inhalation challenge with OVA 61. Conversely, CD8α+β− or CD8α+β+ pDC subsets lead to tolerance induction in the recipient mice as shown by the lack of airway hyperreactivity and airway inflammation in the mice receiving CD8α+β− and CD8α+β+ pDC subsets.

In a different experiment, OVA-loaded subsets of DCs were transferred to the naïve mice followed by OVA/alum sensitization 61. After intranasal challenge, these mice showed reduced airway hyperreactivity, airway inflammation, OVA-specific IgE and Th2 cytokines IL-4 and IL-13 in CD8α+β− and CD8α+β+ pDC subset recipient mice compared to those receiving CD8α−β− pDCs 61. These data confirms that only CD8α+β− and CD8α+β+ pDC subsets are tolerogenic in experimentally induced allergic asthma.

Interestingly, both CD8α+β− and CD8α+β+ are more efficient in inducing FOXP3 expression when co-cultured with naïve OVA-specific CD4+ T cells in the presence of OVA compared to CD8α−β− pDC subset 61. Furthermore, it was found that CD8α+β− and CD8α+β+ pDCs express retinoic acid aldehyde dehydrogenase (RALDH) genes and blocking the function of these enzymes using LE540 abrogated the induction of FOXP3 in T cells (Figure 1).

Figure 1.

Figure 1

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Plasmcytoid dendritic cell (pDC) subsets CD8α−β−, CD8α+β− and CD8α+β+ activate T cell mediated immune responses with opposing effects. CD8α+β− and CD8α+β+ pDC subsets convert naïve T cells into Foxp3+ regulatory T cells (Treg) via several potential mechanisms including expression of Retinaldehyde dehydrogenase (RALDH), indoleamine 2,3 dioxygenase (IDO) to induce tolerance and prevent the induction of airway hyper-reactivity (AHR) and airway inflammation. Moreover, these tolerogenic subsets express high levels of GITR-L which can signal to Treg cells to suppress effector T cells. CD8α−β− pDCs convert naïve T cells into Teff cells to induce AHR and airway inflammation 36.

Mechanisms of tolerogenic effects of pDCs

PDCs contribute to tolerance induction through diverse mechanisms such as facilitating the generation of Treg cells, direct cytotoxicity effects, induction of T cell anergy and clonal deletion of T cells 62–67. PDCs can potentiate the generation of Treg cells by several mechanisms: (I) Indoleamine 2,3 dioxygenase (IDO) is an immunoregulatory tryptophan degrading enzyme originally found to be constitutively expressed and up-regulated by DCs upon stimulation (reviewed in 68). IDO is shown to be involved in tolerance induction in autoimmune disease, transplantation and in fetal and cancer tolerance 24, 69–73. Although it was initially thought that the immunoregulatory function of IDO was through tryptophan deprivation and/or generation of kynurenine and its downstream metabolites (reviewed in 74), it has been recently reported that involvement of IDO in intracellular signaling is important for its immunoregulatory effects and its enzymatic function is dispensable for the mentioned function 75. (II) In a mouse model of allergic asthma it was found that a subpopulation of lung pDCs expresses program cell death ligand-1 (PD-L1) and adoptive transfer of CpG stimulated pDCs from mice lacking PD-L1 fails to suppress the asthma-like symptoms in this model 48. (III) There is evidence indicating that retinoic acid stimulates the induction of FOXP3 in T cells in vitro. It was recently demonstrated that CD8α+β− and pDC subsets express high levels of RALDH enzymes which convert retinol to retinoic acid and that blocking RALDH abrogates pDC-mediated induction of FOXP3+ Treg cells in vitro 61. (IV) Glucocorticoid-induced TNFR-related protein ligand (GITRL) is a T cell costimulatory molecule expressed by a variety of antigen presenting cells including pDCs 76. GITRL on pDCs upon engaging with GITR on Treg cells initiates a bidirectional signal to the Treg cell and to the pDC 77. GITRL:GITR signaling through the pDC has been shown to activate non-canonical NF-κB pathway and induce IDO in experimentally induced allergy in mice 77.

Another mechanism of pDC-mediated tolerance induction is by directly attacking T cells 62–64. It has been reported that a subset of mouse pDCs and ex vivo cultured human pDCs in the presence of IL-3 express granzyme B 62–64. Interestingly, granzyme B+ mouse pDCs were reported to express CD8α and directly attack and clear tumor cells when stimulated with TLR-7 agonist 63. Granzyme B+ human pDCs, however, were shown to have the capacity to directly suppress T cells in the absence of TLR-7 or TLR-9 agonist 64. Therefore, it would be interesting to investigate whether granzyme B+ pDCs play a role in maintaining or restoring tolerance to allergens and whether TLR stimulation can change the direction of pDC cytotoxicity effects towards cell types such as T cells.

A recent study showed that liver pDCs that exhibit higher tolerogenic capacity and produce significantly higher levels of IL-27 than splenic pDCs 78. This study also showed that IL-27 leads to STAT3-medited up-regulation of B7-H1 only in the liver pDCs that can induce FOXP3+ Treg cells 78.

Besides the above-mentioned mechanisms, there is evidence suggesting that pDCs can induce tolerance by anergizing T cells 65, 66. This could be due to low expression of costimulatory molecules by pDCs, since antigenic stimulation through the T cell receptor in the absence of a co-stimulatory signal leads to T cell anergy 79.

Future directions

Given the important roles on pDCs in antiviral immunity and tolerance induction, a detailed understanding of several aspects of pDCs is required for the translational applications of pDCs in allergic diseases. In this regard, it is very important to identify whether the counterpart of CD8α+β−, CD8α+β+ and CD8α+β+ pDC subsets exist in humans. Furthermore, it is important to identify whether these newly described pDC subsets share a common progenitor and to identify the factors deriving each subset. Finally, it is essential to unravel the mechanisms of tolerogenic effects of CD8α+β−, CD8α+β+ and CD8α+β+ pDC subsets for identifying their potential applications in the treatment of human immune diseases.

Acknowledgments

Supported by: NIH R01 AI066020 (O.A.)

References

  • 1.Asselin-Paturel C, Boonstra A, Dalod M, Durand I, Yessaad N, Dezutter-Dambuyant C, et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol. 2001;2:1144–1150. doi: 10.1038/ni736. [DOI] [PubMed] [Google Scholar]
  • 2.Cervantes-Barragan L, Lewis KL, Firner S, Thiel V, Hugues S, Reith W, et al. Plasmacytoid dendritic cells control T-cell response to chronic viral infection. Proc Natl Acad Sci U S A. 2012;109:3012–3017. doi: 10.1073/pnas.1117359109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Davidson S, Kaiko G, Loh Z, Lalwani A, Zhang V, Spann K, et al. Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway. J Immunol. 2011;186:5938–5948. doi: 10.4049/jimmunol.1002635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Boor PP, Metselaar HJ, Jonge S, Mancham S, van der Laan LJ, Kwekkeboom J. Human plasmacytoid dendritic cells induce CD8(+) LAG-3(+) Foxp3(+) CTLA-4(+) regulatory T cells that suppress allo-reactive memory T cells. Eur J Immunol. 2011;41:1663–1674. doi: 10.1002/eji.201041229. [DOI] [PubMed] [Google Scholar]
  • 5.Kavousanaki M, Makrigiannakis A, Boumpas D, Verginis P. Novel role of plasmacytoid dendritic cells in humans: induction of interleukin-10-producing Treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy. Arthritis Rheum. 2010;62:53–63. doi: 10.1002/art.25037. [DOI] [PubMed] [Google Scholar]
  • 6.Martin-Gayo E, Sierra-Filardi E, Corbi AL, Toribio ML. Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood. 2010;115:5366–5375. doi: 10.1182/blood-2009-10-248260. [DOI] [PubMed] [Google Scholar]
  • 7.Lennert K, Remmele W. Karyometric research on lymph node cells in man. I. Germinoblasts, lymphoblasts & lymphocytes. Acta Haematol. 1958;19:99–113. doi: 10.1159/000205419. [DOI] [PubMed] [Google Scholar]
  • 8.Weijer K, Uittenbogaart CH, Voordouw A, Couwenberg F, Seppen J, Blom B, et al. Intrathymic and extrathymic development of human plasmacytoid dendritic cell precursors in vivo. Blood. 2002;99:2752–2759. doi: 10.1182/blood.v99.8.2752. [DOI] [PubMed] [Google Scholar]
  • 9.Bjorck P. Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. Blood. 2001;98:3520–3526. doi: 10.1182/blood.v98.13.3520. [DOI] [PubMed] [Google Scholar]
  • 10.Nakano H, Yanagita M, Gunn MD. CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med. 2001;194:1171–1178. doi: 10.1084/jem.194.8.1171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med. 1997;185:1101–1111. doi: 10.1084/jem.185.6.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863–869. doi: 10.1084/jem.194.6.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7:131–137. doi: 10.1038/ni1303. [DOI] [PubMed] [Google Scholar]
  • 14.Florentin J, Aouar B, Dental C, Thumann C, Firaguay G, Gondois-Rey F, et al. HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells. Blood. 2012;120:4544–4551. doi: 10.1182/blood-2012-02-413286. [DOI] [PubMed] [Google Scholar]
  • 15.Martinet J, Leroy V, Dufeu-Duchesne T, Larrat S, Richard MJ, Zoulim F, et al. Plasmacytoid dendritic cells induce efficient stimulation of antiviral immunity in the context of chronic hepatitis B virus infection. Hepatology. 2012;56:1706–1718. doi: 10.1002/hep.25879. [DOI] [PubMed] [Google Scholar]
  • 16.Wang Y, Swiecki M, Cella M, Alber G, Schreiber RD, Gilfillan S, et al. Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection. Cell Host Microbe. 2012;11:631–642. doi: 10.1016/j.chom.2012.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Fiebiger E, Meraner P, Weber E, Fang IF, Stingl G, Ploegh H, et al. Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells. J Exp Med. 2001;193:881–892. doi: 10.1084/jem.193.8.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Di Pucchio T, Chatterjee B, Smed-Sorensen A, Clayton S, Palazzo A, Montes M, et al. Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I. Nat Immunol. 2008;9:551–557. doi: 10.1038/ni.1602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Chan VS, Nie YJ, Shen N, Yan S, Mok MY, Lau CS. Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus. Autoimmun Rev. 2012;11:890–897. doi: 10.1016/j.autrev.2012.03.004. [DOI] [PubMed] [Google Scholar]
  • 20.Dubois B, Joubert G, Gomez de Aguero M, Gouanvic M, Goubier A, Kaiserlian D. Sequential role of plasmacytoid dendritic cells and regulatory T cells in oral tolerance. Gastroenterology. 2009;137:1019–1028. doi: 10.1053/j.gastro.2009.03.055. [DOI] [PubMed] [Google Scholar]
  • 21.Loschko J, Heink S, Hackl D, Dudziak D, Reindl W, Korn T, et al. Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity. J Immunol. 2011;187:6346–6356. doi: 10.4049/jimmunol.1102307. [DOI] [PubMed] [Google Scholar]
  • 22.Liu X, Mishra P, Yu S, Beckmann J, Wendland M, Kocks J, et al. Tolerance induction towards cardiac allografts under costimulation blockade is impaired in CCR7-deficient animals but can be restored by adoptive transfer of syngeneic plasmacytoid dendritic cells. Eur J Immunol. 2011;41:611–623. doi: 10.1002/eji.201040877. [DOI] [PubMed] [Google Scholar]
  • 23.Meloni F, Giuliano S, Solari N, Draghi P, Miserere S, Bardoni AM, et al. Indoleamine 2,3-dioxygenase in lung allograft tolerance. J Heart Lung Transplant. 2009;28:1185–1192. doi: 10.1016/j.healun.2009.07.023. [DOI] [PubMed] [Google Scholar]
  • 24.Zheng X, Koropatnick J, Chen D, Velenosi T, Ling H, Zhang X, et al. Silencing IDO in dendritic cells: A novel approach to enhance cancer immunotherapy in a murine breast cancer model. Int J Cancer. 2012;132:967–977. doi: 10.1002/ijc.27710. [DOI] [PubMed] [Google Scholar]
  • 25.Sawant A, Hensel JA, Chanda D, Harris BA, Siegal GP, Maheshwari A, et al. Depletion of Plasmacytoid Dendritic Cells Inhibits Tumor Growth and Prevents Bone Metastasis of Breast Cancer Cells. J Immunol. 2012;189:4258–4265. doi: 10.4049/jimmunol.1101855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Della Bella S, Giannelli S, Cozzi V, Signorelli V, Cappelletti M, Cetin I, et al. Incomplete activation of peripheral blood dendritic cells during healthy human pregnancy. Clin Exp Immunol. 2011;164:180–192. doi: 10.1111/j.1365-2249.2011.04330.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, et al. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol. 2010;184:2999–3007. doi: 10.4049/jimmunol.0804106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Manz MG, Traver D, Miyamoto T, Weissman IL, Akashi K. Dendritic cell potentials of early lymphoid and myeloid progenitors. Blood. 2001;97:3333–3341. doi: 10.1182/blood.v97.11.3333. [DOI] [PubMed] [Google Scholar]
  • 29.Sitnicka E, Bryder D, Theilgaard-Monch K, Buza-Vidas N, Adolfsson J, Jacobsen SE. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity. 2002;17:463–472. doi: 10.1016/s1074-7613(02)00419-3. [DOI] [PubMed] [Google Scholar]
  • 30.D'Amico A, Wu L. The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. J Exp Med. 2003;198:293–303. doi: 10.1084/jem.20030107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Vogt TK, Link A, Perrin J, Finke D, Luther SA. Novel function for interleukin-7 in dendritic cell development. Blood. 2009;113:3961–3968. doi: 10.1182/blood-2008-08-176321. [DOI] [PubMed] [Google Scholar]
  • 32.Pelayo R, Hirose J, Huang J, Garrett KP, Delogu A, Busslinger M, et al. Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow. Blood. 2005;105:4407–4415. doi: 10.1182/blood-2004-07-2529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Corcoran L, Ferrero I, Vremec D, Lucas K, Waithman J, O'Keeffe M, et al. The lymphoid past of mouse plasmacytoid cells and thymic dendritic cells. J Immunol. 2003;170:4926–4932. doi: 10.4049/jimmunol.170.10.4926. [DOI] [PubMed] [Google Scholar]
  • 34.Sathe P, Vremec D, Wu L, Corcoran L, Shortman K. Convergent differentiation: myeloid and lymphoid pathways to murine plasmacytoid dendritic cells. Blood. 2013;121:11–19. doi: 10.1182/blood-2012-02-413336. [DOI] [PubMed] [Google Scholar]
  • 35.Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, et al. In vivo analysis of dendritic cell development and homeostasis. Science. 2009;324:392–397. doi: 10.1126/science.1170540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 2006;311:83–87. doi: 10.1126/science.1117729. [DOI] [PubMed] [Google Scholar]
  • 37.Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J Exp Med. 2003;198:305–313. doi: 10.1084/jem.20030323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Liu K, Nussenzweig MC. Origin and development of dendritic cells. Immunol Rev. 2010;234:45–54. doi: 10.1111/j.0105-2896.2009.00879.x. [DOI] [PubMed] [Google Scholar]
  • 39.Waskow C, Liu K, Darrasse-Jeze G, Guermonprez P, Ginhoux F, Merad M, et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol. 2008;9:676–683. doi: 10.1038/ni.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Metcalf D. Hematopoietic cytokines. Blood. 2008;111:485–491. doi: 10.1182/blood-2007-03-079681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Vremec D, Lieschke GJ, Dunn AR, Robb L, Metcalf D, Shortman K. The influence of granulocyte/macrophage colony-stimulating factor on dendritic cell levels in mouse lymphoid organs. Eur J Immunol. 1997;27:40–44. doi: 10.1002/eji.1830270107. [DOI] [PubMed] [Google Scholar]
  • 42.Naik SH, Sathe P, Park HY, Metcalf D, Proietto AI, Dakic A, et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol. 2007;8:1217–1226. doi: 10.1038/ni1522. [DOI] [PubMed] [Google Scholar]
  • 43.Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol. 2007;7:19–30. doi: 10.1038/nri1996. [DOI] [PubMed] [Google Scholar]
  • 44.Greter M, Helft J, Chow A, Hashimoto D, Mortha A, Agudo-Cantero J, et al. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity. 2012;36:1031–1046. doi: 10.1016/j.immuni.2012.03.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Upham JW, Zhang G, Rate A, Yerkovich ST, Kusel M, Sly PD, et al. Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing. J Allergy Clin Immunol. 2009;124:707 e2–713 e2. doi: 10.1016/j.jaci.2009.07.009. [DOI] [PubMed] [Google Scholar]
  • 46.Palomares O, Ruckert B, Jartti T, Kucuksezer UC, Puhakka T, Gomez E, et al. Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance. J Allergy Clin Immunol. 2012;129:510–520. 20 e1–20 e9. doi: 10.1016/j.jaci.2011.09.031. [DOI] [PubMed] [Google Scholar]
  • 47.de Heer HJ, Hammad H, Soullie T, Hijdra D, Vos N, Willart MA, et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med. 2004;200:89–98. doi: 10.1084/jem.20040035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Kool M, van Nimwegen M, Willart MA, Muskens F, Boon L, Smit JJ, et al. An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol. 2009;183:1074–1082. doi: 10.4049/jimmunol.0900471. [DOI] [PubMed] [Google Scholar]
  • 49.Smit JJ, Bol-Schoenmakers M, Hassing I, Fiechter D, Boon L, Bleumink R, et al. The role of intestinal dendritic cells subsets in the establishment of food allergy. Clin Exp Allergy. 2011;41:890–898. doi: 10.1111/j.1365-2222.2011.03738.x. [DOI] [PubMed] [Google Scholar]
  • 50.Johnson TR, Johnson CN, Corbett KS, Edwards GC, Graham BS. Primary human mDC1, mDC2, and pDC dendritic cells are differentially infected and activated by respiratory syncytial virus. PLoS One. 2011;6:e16458. doi: 10.1371/journal.pone.0016458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Konieczna P, Groeger D, Ziegler M, Frei R, Ferstl R, Shanahan F, et al. Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells. Gut. 2012;61:354–366. doi: 10.1136/gutjnl-2011-300936. [DOI] [PubMed] [Google Scholar]
  • 52.Takagi H, Fukaya T, Eizumi K, Sato Y, Sato K, Shibazaki A, et al. Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo. Immunity. 2011;35:958–971. doi: 10.1016/j.immuni.2011.10.014. [DOI] [PubMed] [Google Scholar]
  • 53.Tsuchida T, Matsuse H, Fukahori S, Kawano T, Tomari S, Fukushima C, et al. Effect of respiratory syncytial virus infection on plasmacytoid dendritic cell regulation of allergic airway inflammation. Int Arch Allergy Immunol. 2012;157:21–30. doi: 10.1159/000324676. [DOI] [PubMed] [Google Scholar]
  • 54.Crother TR, Schroder NW, Karlin J, Chen S, Shimada K, Slepenkin A, et al. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells. PLoS One. 2011;6:e20784. doi: 10.1371/journal.pone.0020784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Herbst T, Sichelstiel A, Schar C, Yadava K, Burki K, Cahenzli J, et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med. 2011;184:198–205. doi: 10.1164/rccm.201010-1574OC. [DOI] [PubMed] [Google Scholar]
  • 56.Wendland M, Czeloth N, Mach N, Malissen B, Kremmer E, Pabst O, et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci U S A. 2007;104:6347–6352. doi: 10.1073/pnas.0609180104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Hadeiba H, Sato T, Habtezion A, Oderup C, Pan J, Butcher EC. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol. 2008;9:1253–1260. doi: 10.1038/ni.1658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Schlitzer A, Heiseke AF, Einwachter H, Reindl W, Schiemann M, Manta CP, et al. Tissue-specific differentiation of a circulating CCR9-pDC-like common dendritic cell precursor. Blood. 2012;119:6063–6071. doi: 10.1182/blood-2012-03-418400. [DOI] [PubMed] [Google Scholar]
  • 59.Bjorck P, Leong HX, Engleman EG. Plasmacytoid dendritic cell dichotomy: identification of IFN-alpha producing cells as a phenotypically and functionally distinct subset. J Immunol. 2011;186:1477–1485. doi: 10.4049/jimmunol.1000454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Matsui T, Connolly JE, Michnevitz M, Chaussabel D, Yu CI, Glaser C, et al. CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions. J Immunol. 2009;182:6815–6823. doi: 10.4049/jimmunol.0802008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Lombardi V, Speak AO, Kerzerho J, Szely N, Akbari O. CD8alpha(+)beta(−) and CD8alpha(+)beta(+) plasmacytoid dendritic cells induce Foxp3(+) regulatory T cells and prevent the induction of airway hyper-reactivity. Mucosal Immunol. 2012;5:432–443. doi: 10.1038/mi.2012.20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Bratke K, Nielsen J, Manig F, Klein C, Kuepper M, Geyer S, et al. Functional expression of granzyme B in human plasmacytoid dendritic cells: a role in allergic inflammation. Clin Exp Allergy. 2010;40:1015–1024. doi: 10.1111/j.1365-2222.2010.03499.x. [DOI] [PubMed] [Google Scholar]
  • 63.Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest. 2012;122:575–585. doi: 10.1172/JCI61034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Jahrsdorfer B, Vollmer A, Blackwell SE, Maier J, Sontheimer K, Beyer T, et al. Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion. Blood. 2010;115:1156–1165. doi: 10.1182/blood-2009-07-235382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol. 2006;7:652–662. doi: 10.1038/ni1333. [DOI] [PubMed] [Google Scholar]
  • 66.Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C, et al. Plasmacytoid dendritic cells mediate oral tolerance. Immunity. 2008;29:464–475. doi: 10.1016/j.immuni.2008.06.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Abe M, Wang Z, de Creus A, Thomson AW. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am J Transplant. 2005;5:1808–1819. doi: 10.1111/j.1600-6143.2005.00954.x. [DOI] [PubMed] [Google Scholar]
  • 68.Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4:762–774. doi: 10.1038/nri1457. [DOI] [PubMed] [Google Scholar]
  • 69.Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, Fenoglio D, et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci U S A. 2010;107:11918–11923. doi: 10.1073/pnas.1001749107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.O'Sullivan BJ, Pai S, Street S, An X, MacDonald KP, Wong M, et al. Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation. J Immunol. 2011;187:4018–4030. doi: 10.4049/jimmunol.1101727. [DOI] [PubMed] [Google Scholar]
  • 71.Pigott E, Mandik-Nayak L. Addition of an indoleamine 2,3,-dioxygenase inhibitor to B cell-depletion therapy blocks autoreactive B cell activation and recurrence of arthritis in K/BxN mice. Arthritis Rheum. 2012;64:2169–2178. doi: 10.1002/art.34406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Ravishankar B, Liu H, Shinde R, Chandler P, Baban B, Tanaka M, et al. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2012;109:3909–3914. doi: 10.1073/pnas.1117736109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Chen G, Kheradmand T, Bryant J, Wang S, Tasch J, Wang JJ, et al. Intragraft CD11b(+) IDO(+) Cells Mediate Cardiac Allograft Tolerance by ECDI-Fixed Donor Splenocyte Infusions. Am J Transplant. 2012;12:2920–2929. doi: 10.1111/j.1600-6143.2012.04203.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Grohmann U, Fallarino F, Puccetti P. Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol. 2003;24:242–248. doi: 10.1016/s1471-4906(03)00072-3. [DOI] [PubMed] [Google Scholar]
  • 75.Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol. 2011;12:870–878. doi: 10.1038/ni.2077. [DOI] [PubMed] [Google Scholar]
  • 76.Kim JD, Choi BK, Bae JS, Lee UH, Han IS, Lee HW, et al. Cloning and characterization of GITR ligand. Genes Immun. 2003;4:564–569. doi: 10.1038/sj.gene.6364026. [DOI] [PubMed] [Google Scholar]
  • 77.Grohmann U, Volpi C, Fallarino F, Bozza S, Bianchi R, Vacca C, et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med. 2007;13:579–586. doi: 10.1038/nm1563. [DOI] [PubMed] [Google Scholar]
  • 78.Matta BM, Raimondi G, Rosborough BR, Sumpter TL, Thomson AW. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells. J Immunol. 2012;188:5227–5237. doi: 10.4049/jimmunol.1103382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 2002;23:445–449. doi: 10.1016/s1471-4906(02)02281-0. [DOI] [PubMed] [Google Scholar]

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