Rapamycin Inhibits Innate and Adaptive Immune Functions of Human Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2hiCD5+CD81+pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34+progenitors. These CD2hiCD5+CD81+cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5+CD81+pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5−CD81−pDCs, human CD5+CD81+pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.

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Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets

Blood ◽

10.1182/blood-2012-06-435644 ◽

2013 ◽

Vol 121 (3) ◽

pp. 459-467 ◽

Cited By ~ 97

Author(s):

Jurjen Tel ◽

Gerty Schreibelt ◽

Simone P. Sittig ◽

Till S. M. Mathan ◽

Sonja I. Buschow ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Adaptive Immune System ◽

Plasmacytoid Dendritic Cells ◽

Cell Responses ◽

Adaptive Immune ◽

Antitumor Immunotherapy

Abstract In human peripheral blood, 4 populations of dendritic cells (DCs) can be distinguished, plasmacytoid dendritic cells (pDCs) and CD16+, CD1c+, and BDCA-3+ myeloid DCs (mDCs), each with distinct functional characteristics. DCs have the unique capacity to cross-present exogenously encountered antigens (Ags) to CD8+ T cells. Here we studied the ability of all 4 blood DC subsets to take up, process, and present tumor Ags to T cells. Although pDCs take up less Ags than CD1c+ and BDCA3+ mDCs, pDCs induce potent Ag-specific CD4+ and CD8+ T-cell responses. We show that pDCs can preserve Ags for prolonged periods of time and on stimulation show strong induction of both MHC class I and II, which explains their efficient activation of both CD4+ and CD8+ T cells. Furthermore, pDCs cross-present soluble and cell-associated tumor Ags to cytotoxic T lymphocytes equally well as BDCA3+ mDCs. These findings, and the fact that pDCs outnumber BDCA3+ mDCs, both in peripheral blood and lymph nodes, together with their potent IFN-I production, known to activate both components of the innate and adaptive immune system, put human pDCs forward as potent activators of CD8+ T cells in antitumor responses. Our findings may therefore have important consequences for the development of antitumor immunotherapy.

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Immune functions and recruitment of plasmacytoid dendritic cells in psoriasis

Autoimmunity ◽

10.3109/08916930903510906 ◽

2010 ◽

Vol 43 (3) ◽

pp. 215-219 ◽

Cited By ~ 49

Author(s):

Cristina Albanesi ◽

Claudia Scarponi ◽

Daniela Bosisio ◽

Silvano Sozzani ◽

Giampiero Girolomoni

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Immune Functions

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Plasmacytoid Dendritic Cells in Patients with MGUS and Multiple Myeloma

Journal of Clinical Medicine ◽

10.3390/jcm10163717 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3717

Author(s):

Andrea Knight ◽

Lucie Rihova ◽

Romana Kralova ◽

Miroslav Penka ◽

Zdenek Adam ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Dendritic Cells ◽

Tumor Cells ◽

Plasmacytoid Dendritic Cells ◽

Adaptive Immune ◽

Healthy Donors ◽

Immunosuppressive Tumor Microenvironment ◽

Immune Deficiencies

Background: Plasmacytoid dendritic cells (pDCs) play prominent roles in mediating innate and adaptive immune responses. However, it is unclear how pDCs contribute to the immunosuppressive tumor microenvironment described in multiple myeloma (MM). Methods: Newly diagnosed myeloma patients (MM, n = 37) were analyzed to determine the pDC counts in comparison to peripheral blood (PB, n = 53) and bone marrow (BM, n = 10) samples of age-matched healthy donors (HD) using flow cytometry. Second, proliferation of myeloma tumor cells in the presence of freshly isolated pDCs was examined. Third, production of IFNα by pDCs co-cultured with MM cells was determined by intracellular staining. Results: We found a highly significant reduction of circulating pDCs (p < 0.0001) and in bone marrow (p < 0.0001) of MM patients compared to HD. We also observed a significant decrease of pDCs (p = 0.004) in BM in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 12). Importantly, we determined that pDCs promote proliferation specifically of MM cells and not the stromal cells and that pDCs secrete IFNα upon co-culture with MM tumor cells. Conclusions: Our results show altered pDC frequencies in the BM microenvironment in MGUS and MM patients at diagnosis. We showed the tumor-promoting function of pDCs that may mediate immune deficiencies affecting long-term disease control and treatment outcome.

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Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

Cells ◽

10.3390/cells9020417 ◽

2020 ◽

Vol 9 (2) ◽

pp. 417 ◽

Cited By ~ 5

Author(s):

Matilde Monti ◽

Francesca Consoli ◽

Raffaella Vescovi ◽

Mattia Bugatti ◽

William Vermi

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Published Data ◽

Host Immune System ◽

Type I ◽

Adaptive Immune ◽

Pathway Activation ◽

Long Time ◽

And Function ◽

Early Phases

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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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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Manipulation of dendritic cell functions by human cytomegalovirus

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399408000872 ◽

2008 ◽

Vol 10 ◽

Cited By ~ 18

Author(s):

John Sinclair

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Dendritic Cell ◽

Human Cytomegalovirus ◽

T Cell Activation ◽

Cell Activation ◽

Immune Functions ◽

Th2 Response ◽

Cell Functions ◽

Adaptive Immune

Dendritic cells are the most potent antigen-presenting cells of the mammalian immune system and are central to the initiation and maintenance of the adaptive immune response. They are crucial for the presentation of antigen to T cells and B cells, as well as the induction of chemokines and proinflammatory cytokines, which orchestrate the balance of the cell-mediated (Th1) and antibody (Th2) response. This ability of dendritic cells to present antigen and release chemokines and cytokines also bridges the innate and adaptive immune responses by driving T cell activation. These cells thus possess key immunological functions that make them the front line of defence for the targeting and clearance of any invading pathogen and, as such, they underpin the host immune response to infection. For efficient infection, invading pathogens often need to overcome these sentinel immune functions. It is therefore not surprising that pathogens have evolved numerous mechanisms to target dendritic cell functions directly or indirectly during infection, and at least one herpesvirus – human cytomegalovirus – has evolved a life cycle that hijacks dendritic cells for its long-term persistence in the infected host.

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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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