scholarly journals The Extracellular Domain of CD83 Inhibits Dendritic Cell–mediated T Cell Stimulation and Binds to a Ligand on Dendritic Cells

2001 ◽  
Vol 194 (12) ◽  
pp. 1813-1821 ◽  
Author(s):  
Matthias Lechmann ◽  
Daniëlle J.E.B. Krooshoop ◽  
Diana Dudziak ◽  
Elisabeth Kremmer ◽  
Christine Kuhnt ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Functional Aspects ◽  
T Cell Stimulation ◽  
Ig Superfamily ◽  
Ig Domain ◽  
Dc Maturation

CD83 is an immunoglobulin (Ig) superfamily member that is upregulated during the maturation of dendritic cells (DCs). It has been widely used as a marker for mature DCs, but its function is still unknown. To approach its potential functional role, we have expressed the extracellular Ig domain of human CD83 (hCD83ext) as a soluble protein. Using this tool we could show that immature as well as mature DCs bind to CD83. Since CD83 binds a ligand also expressed on immature DCs, which do not express CD83, indicates that binding is not a homophilic interaction. In addition we demonstrate that hCD83ext interferes with DC maturation downmodulating the expression of CD80 and CD83, while no phenotypical effects were observed on T cells. Finally, we show that hCD83ext inhibits DC-dependent allogeneic and peptide-specific T cell proliferation in a concentration dependent manner in vitro. This is the first report regarding functional aspects of CD83 and the binding of CD83 to DCs.

scholarly journals CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming

2008 ◽  
Vol 205 (11) ◽  
pp. 2561-2574 ◽  
Author(s):  
Alfonso Martín-Fontecha ◽  
Dirk Baumjohann ◽  
Greta Guarda ◽  
Andrea Reboldi ◽  
Miroslav Hons ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Memory T Cells ◽  
Effector Memory ◽  
High Endothelial Venules ◽  
T Cell Priming ◽  
Dc Maturation

There is growing evidence that the maturation state of dendritic cells (DCs) is a critical parameter determining the balance between tolerance and immunity. We report that mouse CD4+ effector memory T (TEM) cells, but not naive or central memory T cells, constitutively expressed CD40L at levels sufficient to induce DC maturation in vitro and in vivo in the absence of antigenic stimulation. CD4+ TEM cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules. Trafficking of CD4+ TEM cells into chronic reactive lymph nodes maintained resident DCs in a mature state and promoted naive T cell responses and experimental autoimmune encephalomyelitis (EAE) to antigens administered in the absence of adjuvants. Antibodies to CD62P, which blocked CD4+ TEM cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE. These results show that TEM cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

Binding of β2–glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1552-1557 ◽  
Author(s):  
Masataka Kuwana ◽  
Eiji Matsuura ◽  
Kazuko Kobayashi ◽  
Yuka Okazaki ◽  
Junichi Kaburaki ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Processing ◽  
T Cell Response ◽  
Autoimmune Response ◽  
Dependent Manner ◽  
Glycoprotein I ◽  
Autoreactive T Cell

Abstract Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)–binding plasma proteins, such as β2-glycoprotein I (β2GPI). We have recently found that CD4+ T cells autoreactive to β2GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53. However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to β2GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in β2GPI is induced as a direct consequence of antigen processing from β2GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound β2GPI induced a response of p276-290–specific CD4+ T-cell lines generated from the patients in an HLA-DR–restricted and antigen-processing–dependent manner but those with β2GPI or PL alone did not. In addition, the p276-290–reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound β2GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to β2GPI and should be useful in clarifying the pathogenesis of APS.

scholarly journals Contact-dependent Stimulation and Inhibition of Dendritic Cells by Natural Killer Cells

2002 ◽  
Vol 195 (3) ◽  
pp. 335-341 ◽  
Author(s):  
Diego Piccioli ◽  
Silverio Sbrana ◽  
Emiliano Melandri ◽  
Nicholas M. Valiante
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Types ◽  
Cell Contact ◽  
Dependent Manner ◽  
Tnf Α ◽  
Dominant Feature ◽  
Dc Maturation

Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a “control switch” for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF-α in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-α/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.

scholarly journals Expression of vFLIP in a Lentiviral Vaccine Vector Activates NF-κB, Matures Dendritic Cells, and Increases CD8+ T-Cell Responses

2008 ◽  
Vol 83 (4) ◽  
pp. 1555-1562 ◽  
Author(s):  
Helen M. Rowe ◽  
Luciene Lopes ◽  
Najmeeyah Brown ◽  
Sofia Efklidou ◽  
Timothy Smallie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Therapy ◽  
T Cell Response ◽  
Vaccine Vector ◽  
Interleukin 12 ◽  
Mouse Bone Marrow ◽  
Dc Maturation

ABSTRACT Lentiviral vectors deliver antigens to dendritic cells (DCs) in vivo, but they do not trigger DC maturation. We therefore expressed a viral protein that constitutively activates NF-κB, vFLIP from Kaposi's sarcoma-associated herpesvirus (KSHV), in a lentivector to mature DCs. vFLIP activated NF-κB in mouse bone marrow-derived DCs in vitro and matured these DCs to a similar extent as lipopolysaccharide; costimulatory markers CD80, CD86, CD40, and ICAM-1 were upregulated and tumor necrosis factor alpha and interleukin-12 secreted. The vFLIP-expressing lentivector also matured DCs in vivo. When we coexpressed vFLIP in a lentivector with ovalbumin (Ova), we found an increased immune response to Ova; up to 10 times more Ova-specific CD8+ T cells secreting gamma interferon were detected in the spleens of vFLIP_Ova-immunized mice than in the spleens of mice immunized with GFP_Ova. Furthermore, this increased CD8+ T-cell response correlated with improved tumor-free survival in a tumor therapy model. A single immunization with vFLIP_Ova also reduced the parasite load when mice were challenged with OVA-Leishmania donovani. In conclusion, vFLIP from KSHV is a DC activator, maturing DCs in vitro and in vivo. This demonstrates that NF-κB activation is sufficient to induce many aspects of DC maturation and that expression of a constitutive NF-κB activator can improve the efficacy of a vaccine vector.

scholarly journals Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract

2013 ◽  
Vol 210 (9) ◽  
pp. 1871-1888 ◽  
Author(s):  
Darren Ruane ◽  
Lucas Brane ◽  
Bernardo Sgarbi Reis ◽  
Cheolho Cheong ◽  
Jordan Poles ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Present Report ◽  
Cellular Migration ◽  
Dependent Manner ◽  
Gi Tract ◽  
Global Challenge ◽  
Cellular Recruitment

Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of α4β7 and CCR9 by Peyer’s patch and mesenteric lymph node (MLN) dendritic cells (DCs) in a retinoic acid–dependent manner. This paradigm, however, cannot be reconciled with reports of GI T cell responses after intranasal (i.n.) delivery of antigens that do not directly target the GI lymphoid tissue. To explore alternative pathways of cellular migration, we have investigated the ability of DCs from mucosal and nonmucosal tissues to recruit lymphocytes to the GI tract. Unexpectedly, we found that lung DCs, like CD103+ MLN DCs, up-regulate the gut-homing integrin α4β7 in vitro and in vivo, and induce T cell migration to the GI tract in vivo. Consistent with a role for this pathway in generating mucosal immune responses, lung DC targeting by i.n. immunization induced protective immunity against enteric challenge with a highly pathogenic strain of Salmonella. The present report demonstrates novel functional evidence of mucosal cross talk mediated by DCs, which has the potential to inform the design of novel vaccines against mucosal pathogens.

Tolerogenic dendritic cells: cytokine modulation comes of age

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1435-1440 ◽  
Author(s):  
Sergio Rutella ◽  
Silvio Danese ◽  
Giuseppe Leone
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Dc Maturation

Dendritic cells (DCs) include a heterogeneous family of professional APCs involved in initiation of immunity and in immunologic tolerance. Specifically, peripheral tolerance can be achieved and maintained by promoting regulatory T-cell (Treg) responses and/or T-cell anergy or deletion. Until recently, immature developmental stages of DC differentiation were believed to induce T-cell anergy or Treg cells, whereas DCs transformed into mature DCs by activation stimuli were thought to represent immunogenic DCs capable of inciting primary T-cell responses. This paradigm has been challenged by the demonstration of Treg-cell expansion by antigen-bearing, fully mature DCs. Similarly, semimature DCs with a distinctive interleukin 10 (IL-10)+IL-12- cytokine production profile might be endowed with tolerogenic functions, supporting the concept that DC maturation per se should no longer be considered as a distinguishing feature of immunogenic as opposed to tolerogenic DCs (TDCs). Cytokine-modulated TDCs reflect an incomplete or altered status of monocyte differentiation and promote in vitro induction of Treg cells and/or in vivo protection from autoimmune diseases. Several growth factors, including IL-10, transforming growth factor β (TGF-β), granulocyte colony-stimulating factor (G-CSF), hepatocyte growth factor (HGF), and vasoactive intestinal peptide (VIP), modulate DC maturation and favor the differentiation of TDCs. From a therapeutic standpoint, cytokine-modulated TDCs might be beneficial for prevention and/or treatment of posttransplantation graft-versus-host disease (GVHD) and autoimmunity.

scholarly journals Silica-Based Nanoparticles Targeting Dendritic Cells for Cancer Immunotherapy

2020 ◽  
Author(s):  
Yajing Liu ◽  
Lintong Yao ◽  
Yun Zhang ◽  
Wenhui shen ◽  
Chunxia Chen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Tumor Immunotherapy ◽  
Cross Presentation ◽  
Dc Maturation

Abstract BackgroundVaccination is a promising anticancer strategy, but the limited delivery routes and short retention of antigens and immunomodulatory agents are problems that need to be solved in vaccine design. Because silicon nanoparticles have a tunable pore size and high loading capacity, they have been used in a variety of drug delivery systems, but their roles in tumor vaccine and tumor immunotherapy need to be examined.MethodsCD40 mAb was attached to mesoporous silica nanoparticles (MSNs) through covalent conjunction, and MSN-CD40/OVA/CpG nanoparticles were examined by Fourier transform-infrared spectroscopy, transmission electron microscopy and nanoparticle analyzer. In vitro functions of nanoparticles were detected by cytotoxicity, cellular uptake, DC maturation, cross-presentation and T cell priming. In vivo functions were monitored by tumor elimination, DC maturation, cross-presentation and T cell activity.ResultsWe encapsulated anti-CD40 monoclonal antibodies, ovalbumin (OVA) antigen, and a toll-like receptor-9 agonist (CpG) in mesoporous silica nanoparticles (MSNs). The resulting MSN-CD40/OVA/CpG nanoparticles were efficiently phagocytized by splenocytes and bone marrow-derived dendritic cells (BMDC). The MSN-CD40/OVA/CpG nanoparticles induced the BMDC to express the costimulatory molecules CD80 and CD86, and release tumor necrosis factor-α. We found that MSN-CD40/OVA/CpG nanoparticles correctly enhanced antigen cross-priming, and stimulated T cell proliferation and interferon γ (IFNγ) production in vitro. In vivo, the MSN-CD40/OVA/CpG nanoparticles strongly increased intracellular IFNγ secretion and its release from OVA257–264 peptide-specific splenocytes into the cell supernatant, induced dendritic cell expression of major histocompatibility complex-II, and stimulated lymphocyte CD80 and CD86 expression. The MSN-CD40/OVA/CpG nanoparticles also inhibited tumor growth, enhanced tumor infiltration of CD8+ and CD4+ T cells, and stimulated IFNγ secretion from splenocytes. In conclusion, we believe these MSN-CD40/OVA/CpG nanoparticles are a promising strategy for improving antigen cross-presentation, cytotoxic T lymphocyte immune activity, and anti-tumor immunotherapy.

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