Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells

Abstract Dendritic cells (DCs) express functional purinergic type 1 receptors, but the effects of adenosine in these antigen-presenting cells have been only marginally investigated. Here, we further characterized the biologic activity of adenosine in immature DCs (iDCs) and lipopolysaccharide (LPS)–matured DCs (mDCs). Chronic stimulation with adenosine enhanced the macropinocytotic activity and the membrane expression of CD80, CD86, major histocompatibility complex (MHC) class I, and HLA-DR molecules on iDCs. Adenosine also increased LPS-induced CD54, CD80, MHC class I, and HLA-DR molecule expression in mDCs. In addition, adenosine dose-dependently inhibited tumor necrosis factor α and interleukin-12 (IL-12) release, whereas it enhanced the secretion of IL-10 from mDCs. The use of selective receptor agonists revealed that the modulation of the cytokine and cell-surface marker profile was due to activation of A2 adenosine receptor. Functionally, adenosine reduced the allostimulatory capacity of iDCs, but not of mDCs. More important, DCs matured in the presence of adenosine had a reduced capacity to induce T helper 1 (Th1) polarization of naive CD4+ T lymphocytes. Finally, adenosine augmented the release of the chemokine CCL17 and inhibited CXCL10 production by mDCs. In aggregate, the results provide initial evidence that adenosine diminishes the capacity of DCs to initiate and amplify Th1 immune responses.

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Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype

Blood ◽

10.1182/blood-2004-08-3228 ◽

2005 ◽

Vol 106 (3) ◽

pp. 946-955 ◽

Cited By ~ 105

Author(s):

Andreas C. Renkl ◽

Julia Wussler ◽

Thomas Ahrens ◽

Käthe Thoma ◽

Shigeyuki Kon ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Interferon Γ ◽

Interleukin 12 ◽

Cell Mediated Immunity ◽

T Helper 1 ◽

Hla Dr ◽

Th1 Cytokine ◽

Factor Α

AbstractOsteopontin (OPN) has been shown to have T helper 1 (Th1) cytokine functions in cell-mediated immunity. Deficiency of OPN is linked to a reduced Th1 immune response in autoimmunity, infectious disease, and delayed-type allergy. Dendritic cells (DCs) are central for the induction of T-cell–mediated immunity, when initially flexible DCs are instructed by priming signals and tissue-derived factors to adopt Th1, Th2, or regulatory T-cell–inducing phenotypes. Although OPN influences the cytokine secretion of T cells and macrophages, its effects on DC polarization remain an important missing link in the understanding of OPN functions in Th1 immunity. Here we demonstrate that OPN promotes the emigration of human DCs from the epidermis and functionally activates myeloid-type DCs, augmenting their expression of HLA-DR, costimulatory, and adhesion molecules. OPN induces their Th1-promoting tumor necrosis factor α (TNF-α) and interleukin-12 (IL-12) secretion, and enhances their allostimulatory capacity. In mixed lymphocyte reactions (MLRs), OPN stimulates IL-12 secretion by DCs, inducing elevated interferon-γ (IFN-γ) production by T cells. Naive Th cells stimulated by OPN-activated DCs show a Th1-polarized cytokine production. Our findings identify OPN as an important tissue-derived factor that DCs encounter when traveling from peripheral sites of activation to secondary lymphatic organs, which induces DC maturation toward a Th1-promoting phenotype.

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Faculty Opinions recommendation of Regulation of MHC class I transport in human dendritic cells and the dendritic-like cell line KG-1.

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

10.3410/f.1013243.189627 ◽

2003 ◽

Author(s):

Sebastian Springer

Keyword(s):

Dendritic Cells ◽

Cell Line ◽

Mhc Class I ◽

Class I ◽

Human Dendritic Cells

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Murine gammaherpesvirus-68 productively infects immature dendritic cells and blocks maturation

Journal of General Virology ◽

10.1099/vir.0.82931-0 ◽

2007 ◽

Vol 88 (7) ◽

pp. 1896-1905 ◽

Cited By ~ 13

Author(s):

Romana Hochreiter ◽

Catherine Ptaschinski ◽

Steven L. Kunkel ◽

Rosemary Rochford

Keyword(s):

Dendritic Cells ◽

Mhc Class I ◽

Viral Reactivation ◽

Class I ◽

Interleukin 12 ◽

Murine Gammaherpesvirus ◽

Immature Dendritic Cells ◽

Gammaherpesvirus 68 ◽

Murine Gammaherpesvirus 68 ◽

Dc Maturation

Many viruses have evolved mechanisms to evade host immunity by subverting the function of dendritic cells (DCs). This study determined whether murine gammaherpesvirus-68 (γHV-68) could infect immature or mature bone-marrow-derived DCs and what effect infection had on DC maturation. It was found that γHV-68 productively infected immature DCs, as evidenced by increased viral titres over time. If DCs were induced to mature by exposure to LPS and then infected with γHV-68, only a small percentage of cells was productively infected. However, limiting-dilution assays to measure viral reactivation demonstrated that the mature DCs were latently infected with γHV-68. Electron microscopy revealed the presence of capsids in the nucleus of immature DCs but not in mature DCs. Interestingly, infection of immature DCs by γHV-68 did not result in upregulation of the co-stimulatory molecules CD80 and CD86 or MHC class I and II, or induce cell migration, suggesting that the virus infection did not induce DC maturation. Furthermore, γHV-68 infection of immature DCs did not result in elevated interleukin-12, an important cytokine in the induction of T-cell responses. Finally, lipopolysaccharide and poly(I : C) stimulation of γHV-68-infected immature DCs did not induce increases in the expression of co-stimulatory molecules and MHC class I or II compared with mock-treated cells, suggesting that γHV-68 infection blocked maturation. Taken together, these data demonstrate that γHV-68 infection of DCs differs depending on the maturation state of the DC. Moreover, the block in DC maturation suggests a possible immunoevasion strategy by γHV-68.

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Long-Peptide Cross-Presentation by Human Dendritic Cells Occurs in Vacuoles by Peptide Exchange on Nascent MHC Class I Molecules

The Journal of Immunology ◽

10.4049/jimmunol.1501574 ◽

2016 ◽

Vol 196 (4) ◽

pp. 1711-1720 ◽

Cited By ~ 24

Author(s):

Wenbin Ma ◽

Yi Zhang ◽

Nathalie Vigneron ◽

Vincent Stroobant ◽

Kris Thielemans ◽

...

Keyword(s):

Dendritic Cells ◽

Mhc Class I ◽

Class I ◽

Cross Presentation ◽

Peptide Exchange ◽

Human Dendritic Cells ◽

Mhc Class I Molecules

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IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Blood ◽

10.1182/blood-2011-06-363564 ◽

2012 ◽

Vol 119 (6) ◽

pp. 1407-1417 ◽

Cited By ~ 87

Author(s):

Francesca Spadaro ◽

Caterina Lapenta ◽

Simona Donati ◽

Laura Abalsamo ◽

Vincenzo Barnaba ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Tumor Development ◽

Class I ◽

Cross Presentation ◽

The Cross ◽

Human Dendritic Cells

Abstract Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8+ T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8+ T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing–dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.

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Influenza Virus and Poly(I:C) Inhibit MHC Class I-Restricted Presentation of Cell-Associated Antigens Derived from Infected Dead Cells Captured by Human Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.0801720 ◽

2009 ◽

Vol 182 (5) ◽

pp. 2766-2776 ◽

Cited By ~ 16

Author(s):

Davor Frleta ◽

Chun I. Yu ◽

Eynav Klechevsky ◽

Anne-Laure Flamar ◽

Gerard Zurawski ◽

...

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Mhc Class I ◽

Class I ◽

Poly I:C ◽

Human Dendritic Cells

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Mesoporous Silicon Microparticles Enhance MHC Class I Cross-Antigen Presentation by Human Dendritic Cells

Clinical and Developmental Immunology ◽

10.1155/2013/362163 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 19

Author(s):

A. Jiménez-Periáñez ◽

B. Abos Gracia ◽

J. López Relaño ◽

C. M. Diez-Rivero ◽

P. A. Reche ◽

...

Keyword(s):

Dendritic Cells ◽

T Lymphocytes ◽

Mhc Class I ◽

Cytotoxic T Lymphocytes ◽

Class I ◽

Antigenic Peptides ◽

Mesoporous Silicon ◽

Human Dendritic Cells ◽

Antigen Presenting ◽

First Time

The mesoporous silicon microparticles (MSMPs) are excellent vehicles for releasing molecules inside the cell. The aim of this work was to use MSMPs to deliver viral specific MHC class I restricted epitopes into human antigen presenting cells (monocyte derived dendritic cells, MDDCs) to facilitate their capture, processing, and presentation to CD8+ (cytotoxic) T lymphocytes. We show for the first time that MSMPs vehiculation of antigenic peptides enhances their MHC class I presentation by human MDDCs to CD8 T lymphocytes.

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Development of Interleukin-12-Producing Capacity throughout Childhood

Infection and Immunity ◽

10.1128/iai.70.12.6583-6588.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6583-6588 ◽

Cited By ~ 168

Author(s):

John W. Upham ◽

Peter T. Lee ◽

Barbara J. Holt ◽

Tricia Heaton ◽

Susan L. Prescott ◽

...

Keyword(s):

Dendritic Cells ◽

Mononuclear Cells ◽

Cell Function ◽

Intrinsic Property ◽

Interleukin 12 ◽

Peripheral Blood Mononuclear ◽

Hla Dr ◽

Macrophage Colony ◽

Synthetic Capacity ◽

Th1 Immune Responses

ABSTRACT Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5- and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR+ cells that lacked B-cell- and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.

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