Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells. A distinctive feature of pDCs is the production of high amount of type I Interferon (I-IFN), through the Toll-like receptor (TLR) 7 and 9 signaling pathway activation. However, published data indicate that melanoma-associated escape mechanisms are in place to hijack pDC functions. We have recently reported that pDC recruitment is recurrent in the early phases of melanoma, but the entire pDC compartment collapses over melanoma progression. Here, we summarize recent advances on pDC biology and function within the context of melanoma immunity.

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TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

Blood ◽

10.1182/blood-2009-04-216770 ◽

2009 ◽

Vol 114 (9) ◽

pp. 1794-1802 ◽

Cited By ~ 67

Author(s):

Jérémy Di Domizio ◽

Ariane Blum ◽

Maighread Gallagher-Gambarelli ◽

Jean-Paul Molens ◽

Laurence Chaperot ◽

...

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

P38mapk Pathway ◽

Inducible Genes ◽

Level Production ◽

Early Phases ◽

Tlr7 Stimulation

On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only low-level production of IFN-α. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, was independent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7 triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response.

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Cell-intrinsic role for IFN-α–STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response

Blood ◽

10.1182/blood-2011-04-349761 ◽

2011 ◽

Vol 118 (14) ◽

pp. 3879-3889 ◽

Cited By ~ 32

Author(s):

Haiyan S. Li ◽

Alexander Gelbard ◽

Gustavo J. Martinez ◽

Eiji Esashi ◽

Huiyuan Zhang ◽

...

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Type I ◽

Toll Like Receptor ◽

Ccr9 Expression ◽

A Cell ◽

And Function ◽

Antigen Presenting

Abstract Plasmacytoid dendritic cells (pDCs) reside in bone marrrow and lymphoid organs in homeostatic conditions and typically secrete abundant quantities of type I interferons (IFNs) on Toll-like receptor triggering. Recently, a pDC population was identified within Peyer patches (PPs) of the gut that is distinguished by its lack of IFN production; however, the relationship of PP pDCs to pDCs in other organs has been unclear. We report that PP pDCs are derived from common DC progenitors and accumulate in response to Fms-like tyrosine kinase 3 ligand, yet appear divergent in transcription factor profile and surface marker phenotype, including reduced E2-2 and CCR9 expression. Type I IFN signaling via STAT1 has a cell-autonomous role in accrual of PP pDCs in vivo. Moreover, IFN-α enhances pDC generation from DC progenitors by a STAT1-dependent mechanism. pDCs that have been developed in the presence of IFN-α resemble PP pDCs, produce inflammatory cytokines, stimulate Th17 cell generation, and fail to secrete IFN-α on Toll-like receptor engagement. These results indicate that IFN-α influences the development and function of pDCs by inducing emergence of an inflammatory (Th17-inducing) antigen-presenting subset, and simultaneously regulating accumulation of pDCs in the intestinal microenvironment.

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Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells

Blood ◽

10.1182/blood-2003-06-1959 ◽

2004 ◽

Vol 103 (4) ◽

pp. 1391-1397 ◽

Cited By ~ 118

Author(s):

Max Schnurr ◽

Tracey Toy ◽

Amanda Shin ◽

Gunther Hartmann ◽

Simon Rothenfusser ◽

...

Keyword(s):

Dendritic Cells ◽

Adenosine Receptors ◽

Plasmacytoid Dendritic Cells ◽

Receptor Expression ◽

Type I ◽

Cpg Oligodeoxynucleotides ◽

A2a Receptor ◽

A1 Receptor ◽

And Function

Abstract Plasmacytoid dendritic cells (PDCs) are potent regulators of immune function and the major source of type I interferon (IFN) following viral infection. PDCs are found at sites of inflammation in allergic reactions, autoimmune disorders, and cancer, but the mechanisms leading to the recruitment of PDCs to these sites remain elusive. During inflammation, adenosine is released and functions as a signaling molecule via adenosine receptors. This study analyzes adenosine receptor expression and function in human PDCs. Adenosine was found to be a potent chemotactic stimulus for immature PDCs via an A1 receptor–mediated mechanism. The migratory response toward adenosine was comparable to that seen with CXCL12 (stromal-derived factor-1α [SDF-1α), the most potent chemotactic stimulus identified thus far for immature PDCs. Upon maturation, PDCs down-regulate the A1 receptor, resulting in a loss of migratory function. In contrast, mature PDCs up-regulate the A2a receptor, which is positively coupled to adenylyl cyclase and has been implicated in the down-regulation of DC cytokine-producing capacity. We show that in mature PDCs adenosine reduces interleukin-6 (IL-6), IL-12, and IFN-α production in response to CpG oligodeoxynucleotides (ODN). These findings indicate that adenosine may play a dual role in PDC-mediated immunity by initially recruiting immature PDCs to sites of inflammation and by subsequently limiting the extent of the inflammatory response induced by mature PDCs by inhibiting their cytokine-producing capacity.

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Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity

Clinical and Developmental Immunology ◽

10.1155/2008/106321 ◽

2008 ◽

Vol 2008 ◽

pp. 1-10 ◽

Cited By ~ 20

Author(s):

Jorge Schettini ◽

Pinku Mukherjee

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Tumor Antigens ◽

Physiological Role ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Therapeutic Approaches ◽

Adaptive Immune ◽

Type I Ifns

Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients.

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Activation of influenza virus–specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity

Blood ◽

10.1182/blood-2002-10-3063 ◽

2003 ◽

Vol 101 (9) ◽

pp. 3520-3526 ◽

Cited By ~ 234

Author(s):

Jean-François Fonteneau ◽

Michel Gilliet ◽

Marie Larsson ◽

Ida Dasilva ◽

Christian Münz ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Influenza Virus ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Cell Responses ◽

Adaptive Immune

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons (IFNs) upon exposure to enveloped viruses. However, their role in adaptive immune responses, such as the initiation of antiviral T-cell responses, is not known. In this study, we examined interactions between blood pDCs and influenza virus with special attention to the capacity of pDCs to activate influenza-specific T cells. pDCs were compared with CD11c+ DCs, the most potent antigen-presenting cells (APCs), for their capacity to activate T-cell responses. We found that like CD11c+ DCs, pDCs mature following exposure to influenza virus, express CCR7, and produce proinflammatory chemokines, but differ in that they produce type I IFN and are resistant to the cytopathic effect of the infection. After influenza virus exposure, both DC types exhibited an equivalent efficiency to expand anti–influenza virus cytotoxic T lymphocytes (CTLs) and T helper 1 (TH1) CD4+ T cells. Our results pinpoint a new role of pDCs in the induction of antiviral T-cell responses and suggest that these DCs play a prominent role in the adaptive immune response against viruses.

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PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4808 ◽

2008 ◽

Vol 31 (4) ◽

pp. 13

Author(s):

Martin Hyrcza ◽

Mario Ostrowski ◽

Sandy Der

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Hiv Infection ◽

Gene Transcription ◽

Sendai Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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Faculty Opinions recommendation of Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123432.582895 ◽

2008 ◽

Author(s):

Adolfo Garcia-Sastre

Keyword(s):

Dendritic Cells ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Toll Like Receptor

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Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

Science Immunology ◽

10.1126/sciimmunol.abc7302 ◽

2021 ◽

Vol 6 (58) ◽

pp. eabc7302

Author(s):

Tae Jin Yun ◽

Suzu Igarashi ◽

Haoquan Zhao ◽

Oriana A. Perez ◽

Marcus R. Pereira ◽

...

Keyword(s):

Dendritic Cells ◽

Virus Detection ◽

Plasmacytoid Dendritic Cells ◽

Lung Epithelial Cells ◽

Live Cells ◽

Type I ◽

Antiviral Immune Response ◽

Lung Epithelial ◽

Functional Consequences ◽

Infected Cells

Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.

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Lymphocytoid Choriomeningitis Virus Activates Plasmacytoid Dendritic Cells and Induces a Cytotoxic T-Cell Response via MyD88

Journal of Virology ◽

10.1128/jvi.01640-07 ◽

2007 ◽

Vol 82 (1) ◽

pp. 196-206 ◽

Cited By ~ 92

Author(s):

Andreas Jung ◽

Hiroki Kato ◽

Yutaro Kumagai ◽

Himanshu Kumar ◽

Taro Kawai ◽

...

Keyword(s):

Dendritic Cells ◽

Intracellular Signaling ◽

Plasmacytoid Dendritic Cells ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Type I ◽

Ctl Response ◽

Type I Ifns ◽

Lcmv Infection

ABSTRACTToll-like receptors (TLRs) and retinoic acid-inducible gene I-like helicases (RLHs) are two major machineries recognizing RNA virus infection of innate immune cells. Intracellular signaling for TLRs and RLHs is mediated by their cytoplasmic adaptors, i.e., MyD88 or TRIF and IPS-1, respectively. In the present study, we investigated the contributions of TLRs and RLHs to the cytotoxic T-lymphocyte (CTL) response by using lymphocytoid choriomeningitis virus (LCMV) as a model virus. The generation of virus-specific cytotoxic T lymphocytes was critically dependent on MyD88 but not on IPS-1. Type I interferons (IFNs) are known to be important for the development of the CTL response to LCMV infection. Serum levels of type I IFNs and proinflammatory cytokines were mainly dependent on the presence of MyD88, although IPS-1−/−mice showed a decrease in IFN-α levels but not in IFN-β and proinflammatory cytokine levels. Analysis ofIfna6+/GFPreporter mice revealed that plasmacytoid dendritic cells (DCs) are the major source of IFN-α in LCMV infection. MyD88−/−mice were highly susceptible to LCMV infection in vivo. These results suggest that recognition of LCMV by plasmacytoid DCs via TLRs is responsible for the production of type I IFNs in vivo. Furthermore, the activation of a MyD88-dependent innate mechanism induces a CTL response, which eventually leads to virus elimination.

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