S1PR4 is required for plasmacytoid dendritic cell differentiation

Abstract The sphingolipid sphingosine-1-phosphate (S1P) has various functions in immune cell biology, regulating survival, proliferation, and, most prominently, migration. S1P couples to five G protein-coupled receptors (S1PR1–5) to transduce its effects on immune cell function. Expression of S1PR4 is restricted to immune cells. However, its impact on immune cell biology is largely elusive. In the current study, we intended to answer the question of whether S1P might affect plasmacytoid dendritic cell (pDC) migration, which dominantly express S1PR4. pDC are highly specialized cells producing large amounts of type I interferon in response to TLR7/9 ligands after viral infection or during autoimmunity. Surprisingly, we noticed a reduced abundance of pDC, particularly CD4- pDC, in all organs of S1PR4-deficient vs. wildtype mice. This effect was not caused by altered migration of mature pDC, but rather a reduced potential of pDC progenitors, especially common DC progenitors, to differentiate into pDCs. In vitro studies suggested that reduced S1PR4-deficient pDC progenitor differentiation into mature pDC might be explained by both migration and differentiation of pDC progenitors in the bone marrow. As S1PR4 also affected the differentiation of CD34+ human hematopoietic stem cells into pDC, interfering with S1PR4 might be useful to reduce pDC numbers during autoimmunity.

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Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

Journal of Experimental Medicine ◽

10.1084/jem.20080718 ◽

2008 ◽

Vol 205 (13) ◽

pp. 3187-3199 ◽

Cited By ~ 43

Author(s):

Lee-Hwa Tai ◽

Marie-Line Goulet ◽

Simon Belanger ◽

Noriko Toyama-Sorimachi ◽

Nassima Fodil-Cornu ◽

...

Keyword(s):

Immune Responses ◽

Cell Function ◽

Viral Infections ◽

Plasmacytoid Dendritic Cell ◽

Class I ◽

Type I ◽

Class I Mhc ◽

Mhc Molecules

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.

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Inhibitory oligodeoxynucleotides downregulate herpes simplex virus-induced plasmacytoid dendritic cell type I interferon production and modulate cell function

Human Immunology ◽

10.1016/j.humimm.2007.10.008 ◽

2007 ◽

Vol 68 (11) ◽

pp. 879-887 ◽

Cited By ~ 8

Author(s):

Wen-Ming Peng ◽

Chun-Feng Yu ◽

Jean-Pierre Allam ◽

Johannes Oldenburg ◽

Thomas Bieber ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Dendritic Cell ◽

Cell Function ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cell ◽

Type I ◽

Interferon Production ◽

Cell Type ◽

Simplex Virus

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Spi-B is critical for plasmacytoid dendritic cell function and development

Blood ◽

10.1182/blood-2012-06-436527 ◽

2012 ◽

Vol 120 (24) ◽

pp. 4733-4743 ◽

Cited By ~ 42

Author(s):

Izumi Sasaki ◽

Katsuaki Hoshino ◽

Takahiro Sugiyama ◽

Chihiro Yamazaki ◽

Takahiro Yano ◽

...

Keyword(s):

Transcription Factor ◽

Dendritic Cell ◽

Molecular Mechanisms ◽

Cell Function ◽

Plasmacytoid Dendritic Cell ◽

Cell Subset ◽

Type I ◽

Dendritic Cell Subset ◽

Type I Ifn ◽

Deficient Mice

Abstract Plasmacytoid dendritic cells (pDCs), originating from hematopoietic progenitor cells in the BM, are a unique dendritic cell subset that can produce large amounts of type I IFNs by signaling through the nucleic acid–sensing TLR7 and TLR9 (TLR7/9). The molecular mechanisms for pDC function and development remain largely unknown. In the present study, we focused on an Ets family transcription factor, Spi-B, that is highly expressed in pDCs. Spi-B could transactivate the type I IFN promoters in synergy with IFN regulatory factor 7 (IRF-7), which is an essential transcription factor for TLR7/9-induced type I IFN production in pDCs. Spi-B–deficient pDCs and mice showed defects in TLR7/9-induced type I IFN production. Furthermore, in Spi-B–deficient mice, BM pDCs were decreased and showed attenuated expression of a set of pDC-specific genes whereas peripheral pDCs were increased; this uneven distribution was likely because of defective retainment of mature nondividing pDCs in the BM. The expression pattern of cell-surface molecules in Spi-B–deficient mice indicated the involvement of Spi-B in pDC development. The developmental defects of pDCs in Spi-B–deficient mice were more prominent in the BM than in the peripheral lymphoid organs and were intrinsic to pDCs. We conclude that Spi-B plays critical roles in pDC function and development.

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Sphingosine-1-Phosphate Modulates Dendritic Cell Function: Focus on Non-Migratory Effects in Vitro and in Vivo

Cellular Physiology and Biochemistry ◽

10.1159/000362982 ◽

2014 ◽

Vol 34 (1) ◽

pp. 27-44 ◽

Cited By ~ 24

Author(s):

Olga Arlt ◽

Anja Schwiebs ◽

Lukasz Japtok ◽

Katja Rüger ◽

Elisabeth Katzy ◽

...

Keyword(s):

Dendritic Cell ◽

Cell Function ◽

Dendritic Cell Function ◽

Sphingosine 1 Phosphate

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Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia

Blood ◽

10.1182/blood-2003-09-3220 ◽

2004 ◽

Vol 103 (12) ◽

pp. 4666-4668 ◽

Cited By ~ 44

Author(s):

Mohamad Mohty ◽

Eric Jourdan ◽

Naira Ben Mami ◽

Norbert Vey ◽

Ghandi Damaj ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Function ◽

Plasmacytoid Dendritic Cell ◽

Molecular Response ◽

Imatinib Treatment ◽

Type I ◽

Immune Functions

Abstract Plasmacytoid dendritic cells (PDCs) are crucial effectors in innate immunity. In this study, we show that imatinib, a potent inhibitor of BCR/ABL tyrosine kinase activity, in the presence of Flt3-Ligand, could induce CD34+ progenitors from chronic myeloid leukemia (CML) to give rise in vitro to typical BDCA-2+ type I interferon-producing PDCs. The effect of imatinib on PDC generation was related to up-regulation of Flt3 on leukemic CD34+ progenitors. Moreover, patients with chronic myeloid leukemia (CML) who were in complete cytogenetic or molecular response after imatinib treatment restored their blood PDCs both quantitatively and functionally comparable to healthy donors, in contrast to patients not responding to imatinib, further confirming that disease response to imatinib is accompanied by restoration of PDC function in vivo. These findings provide evidence that response to imatinib is capable to restore some DC-related immune functions in CML that might be beneficial for long-term disease control. (Blood. 2004;103:4666-4668)

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Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214991 ◽

2019 ◽

Vol 78 (9) ◽

pp. 1249-1259 ◽

Cited By ~ 6

Author(s):

Alsya J Affandi ◽

Tiago Carvalheiro ◽

Andrea Ottria ◽

Jasper CA Broen ◽

Lara Bossini-Castillo ◽

...

Keyword(s):

Transcription Factor ◽

Systemic Sclerosis ◽

Dendritic Cell ◽

Cell Function ◽

Methylation Status ◽

Skin Fibrosis ◽

Functional Assay ◽

Type I

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology.MethodsIn total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre:Runx3f/f mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model.ResultsHere, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis.ConclusionsWe show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease.

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Constitutive IFN signaling to modulate the immunogenicity of glioma cells.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13528 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13528-e13528

Author(s):

Patrick Roth ◽

Sara Nagy ◽

Caroline Happold ◽

Hannah Schneider ◽

Michael Weller ◽

...

Keyword(s):

Cellular Proliferation ◽

Cell Function ◽

Immune Cell ◽

Acute Infection ◽

Constitutive Expression ◽

Glioma Cells ◽

Type I ◽

Type I Ifn

e13528 Background: Interferons (IFN) are cytokines that might be constitutively expressed also in the absence of acute infection and thereby regulate various physiological processes such as cellular proliferation and differentiation, cell viability or immune cell function. Alterations in IFN signaling have been observed in numerous malignancies, but their role in glioblastoma, particularly in glioma-initiating cells, has not been investigated in detail. Methods: We characterized constitutive type I IFN signaling and its functional impact in glioma cells using expression analyses, RNA interference-mediated silencing of various genes involved in the IFN signaling pathway and immune cell lysis assays. Results: We found constitutive expression of pSTAT1 and Myxovirus A (MxA), a classical IFN-response marker, in the absence of exogenous IFN-β in vitro and higher MxA expression in gliomas than in normal tissue in vivo, indicating that IFN signaling is constitutively active in these tumors. Silencing of the type I IFN receptor, IFNAR1/2, or its ligands, IFN-α or IFN-β, decreased MxA levels, providing evidence for the existence of an autocrine type I IFN signaling loop. On a functional level, we observed reduced PD-L1, MHC class I and class II expression and increased susceptibility to immune cell-mediated lysis upon disruption of IFN signaling, suggesting that constitutive IFN signaling in gliomas contributes to the immune evasion of glioma cells. Conclusions: Our findings point to an important role of constitutive IFN signaling in glioma cells in the regulation of anti-tumor immune responses.

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The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

Blood ◽

10.1182/blood-2013-03-484642 ◽

2013 ◽

Vol 122 (7) ◽

pp. 1192-1202 ◽

Cited By ~ 170

Author(s):

Annkristin Heine ◽

Stefanie Andrea Erika Held ◽

Solveig Nora Daecke ◽

Stephanie Wallner ◽

Sowmya Parampalli Yajnanarayana ◽

...

Keyword(s):

Dendritic Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Jak Inhibitor ◽

Dendritic Cell Differentiation ◽

Key Points ◽

And Function

Key PointsThe JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.

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Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches

Cancers ◽

10.3390/cancers13071577 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1577

Author(s):

Matteo Tanzi ◽

Michela Consonni ◽

Michela Falco ◽

Federica Ferulli ◽

Enrica Montini ◽

...

Keyword(s):

Acute Leukemia ◽

Nk Cells ◽

Tumor Cells ◽

Cell Function ◽

Nk Cell ◽

Autologous Tumor ◽

Lymphoid Leukemia ◽

Hematopoietic Stem ◽

Solid Malignancies

The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients’ myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients’ non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies.

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