Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

Zou, Tong; Caton, Andrew J.; Koretzky, Gary A.; Kambayashi, Taku

doi:10.4049/jimmunol.0903740

Cited by 68 publications

(89 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although specific antigen-dependent interactions do not appear to be required to mediate DC immunoregulatory functions [36,37], our data indicate that in vitro DC antigen specification can target diabetogenic T cells and convey tolerogenic signals. Indeed, it has been shown that antigenprimed DCs induce better protection in NOD mice and that cognate antigen-MCH class II complexes enhance IL-2 induced Treg proliferation [37][38][39].…”

Section: Discussionmentioning

confidence: 74%

See 1 more Smart Citation

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. Methods Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14 + cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14− cell were cocultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed.Results MSC-and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-β, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3 + regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. Conclusions/interpretation In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.

show abstract

Section: Discussionmentioning

confidence: 74%

“…Indeed, it has been shown that antigenprimed DCs induce better protection in NOD mice and that cognate antigen-MCH class II complexes enhance IL-2 induced Treg proliferation [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that DCs are crucial for the induction of T regs and that the extent of T reg induction is determined by the maturation state of the DCs (27,29,30,75). Thus, Banerjee et al showed that CC-DCs are capable of high T reg induction (up to 10% Foxp3 + CD4 + T cells) (27,29).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Regulatory T Cell Function by Monocyte-Derived Dendritic Cells Matured through Electroporation with mRNA Encoding CD40 Ligand, Constitutively Active TLR4, and CD70

Pen

Keersmaecker

Maenhout

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Regulatory T cells (Tregs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)–based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the Treg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active TLR4 (caTLR4) and CD40 ligand (DiMix-DCs), or these factors together with mRNA encoding the costimulatory molecule CD70 (TriMix-DCs) with DCs maturated in the presence of a mixture of inflammatory cytokines (DCs maturated with a combination of the cytokines IL-1β, IL-6, TNF-α, and PGE2) for their ability to counteract Tregs on different levels. We first demonstrated that there was no difference in the extent of Treg induction starting from CD4+CD25− T cells under the influence of the different DC maturation stimuli. Second, we showed that both DiMix- and TriMix-DCs could partly alleviate Treg inhibition of CD8+ T cells. Third, we observed that CD8+ T cells that had been precultured with DiMix-DCs or TriMix-DCs were partially protected against subsequent Treg suppression. Finally, we showed that Tregs cocultured in the presence of TriMix-DCs, but not DiMix-DCs, partially lost their suppressive capacity. This was accompanied by a decrease in CD27 and CD25 expression on Tregs, as well as an increase in the expression of T-bet and secretion of IFN-γ, TNF-α, and IL-10, suggesting a shift of the Treg phenotype toward a Th1 phenotype. In conclusion, these data suggest that TriMix-DCs are not only able to suppress Treg functions, but moreover could be able to reprogram Tregs to Th1 cells under certain circumstances.

show abstract

“…Once migration is achieved, smDC have been shown to mediate auto-and alloimmune tolerance by the preferential expansion of Ag-specific IL-2-dependent CD4 + CD25 + Foxp3 + Treg cells (8,(15)(16)(17)(18). In fact, in the context of a tolerizing DC phenotype, an intact IL-2 activation pathway has been shown to be essential for Treg differentiation (19,20). In addition to the prototypical CD4 + CD25 + Foxp3 + phenotype, Foxp3 appears to drive CD39 expression, an ectonucleotidase that hydrolyzes extracellular ATP and whose catalytic activity is strongly enhanced by TCR ligation; CD39 expression has been shown to be specifically relevant to Treg protection in the context of transplantation immunology (21).…”

Section: Endritic Cells (Dc) Undergo Transition From Immature DCmentioning

confidence: 99%

α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

Ozeri

Mizrahi

Shahaf

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Tolerogenic IL-10–positive CCR7-positive dendritic cells (DC) promote T regulatory (Treg) cell differentiation upon CCR7-dependent migration to draining lymph nodes (DLN). Indeed, in human DC deficiencies, Treg levels are low. α-1 antitrypsin (AAT) has been shown to reduce inflammatory markers, promote a semimature LPS-induced DC phenotype, facilitate Treg expansion, and protect pancreatic islets from alloimmune and autoimmune responses in mice. However, the mechanism behind these activities of AAT is poorly understood. In this study, we examine interactions among DC, CD4+ T cells, and AAT in vitro and in vivo. IL-1β/IFN-γ–mediated DC maturation and effect on Treg development were examined using OT-II cells and human AAT (0.5 mg/ml). CCL19/21-dependent migration of isolated DC and resident islet DC was assessed, and CCR7 surface levels were examined. Migration toward DLN was evaluated by FITC skin painting, transgenic GFP skin tissue grafting, and footpad DC injection. AAT-treated stimulated DC displayed reduced MHC class II, CD40, CD86, and IL-6, but produced more IL-10 and maintained inducible CCR7. Upon exposure of CD4+ T cells to OVA-loaded AAT-treated DC, 2.7-fold more Foxp3+ Treg cells were obtained. AAT-treated cells displayed enhanced chemokine-dependent migration and low surface CD40. Under AAT treatment (60 mg/kg), DLN contained twice more fluorescence after FITC skin painting and twice more donor DC after footpad injection, whereas migrating DC expressed less CD40, MHC class II, and CD86. Intracellular DC IL-10 was 2-fold higher in the AAT group. Taken together, these results suggest that inducible functional CCR7 is maintained during AAT-mediated anti-inflammatory conditions. Further studies are required to elucidate the mechanism behind the favorable tolerogenic activities of AAT.

show abstract

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

Abstract: Material Supplementary 0.DC1http://www.jimmunol.org/content/suppl/2010/08/04/jimmunol.090374

Cited by 68 publications

References 42 publications

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

Modulation of Regulatory T Cell Function by Monocyte-Derived Dendritic Cells Matured through Electroporation with mRNA Encoding CD40 Ligand, Constitutively Active TLR4, and CD70

α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

Contact Info

Product

Resources

About