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Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion

Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3(+) induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costim...

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Autores principales: Silva-Vilches, Cinthia, Pletinckx, Katrien, Lohnert, Miriam, Pavlovic, Vladimir, Ashour, Diyaaeldin, John, Vini, Vendelova, Emilia, Kneitz, Susanne, Zhou, Jie, Chen, Rena, Reinheckel, Thomas, Mueller, Thomas D., Bodem, Jochen, Lutz, Manfred B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536293/
https://www.ncbi.nlm.nih.gov/pubmed/28759565
http://dx.doi.org/10.1371/journal.pone.0178114
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author Silva-Vilches, Cinthia
Pletinckx, Katrien
Lohnert, Miriam
Pavlovic, Vladimir
Ashour, Diyaaeldin
John, Vini
Vendelova, Emilia
Kneitz, Susanne
Zhou, Jie
Chen, Rena
Reinheckel, Thomas
Mueller, Thomas D.
Bodem, Jochen
Lutz, Manfred B.
author_facet Silva-Vilches, Cinthia
Pletinckx, Katrien
Lohnert, Miriam
Pavlovic, Vladimir
Ashour, Diyaaeldin
John, Vini
Vendelova, Emilia
Kneitz, Susanne
Zhou, Jie
Chen, Rena
Reinheckel, Thomas
Mueller, Thomas D.
Bodem, Jochen
Lutz, Manfred B.
author_sort Silva-Vilches, Cinthia
collection PubMed
description Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3(+) induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CT(hi), CT(lo)) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CT(hi) conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CT(lo)- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3(+) iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CT(lo)- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3(+) Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.
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spelling pubmed-55362932017-08-07 Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion Silva-Vilches, Cinthia Pletinckx, Katrien Lohnert, Miriam Pavlovic, Vladimir Ashour, Diyaaeldin John, Vini Vendelova, Emilia Kneitz, Susanne Zhou, Jie Chen, Rena Reinheckel, Thomas Mueller, Thomas D. Bodem, Jochen Lutz, Manfred B. PLoS One Research Article Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3(+) induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CT(hi), CT(lo)) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CT(hi) conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CT(lo)- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3(+) iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CT(lo)- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3(+) Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae. Public Library of Science 2017-07-31 /pmc/articles/PMC5536293/ /pubmed/28759565 http://dx.doi.org/10.1371/journal.pone.0178114 Text en © 2017 Silva-Vilches et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Silva-Vilches, Cinthia
Pletinckx, Katrien
Lohnert, Miriam
Pavlovic, Vladimir
Ashour, Diyaaeldin
John, Vini
Vendelova, Emilia
Kneitz, Susanne
Zhou, Jie
Chen, Rena
Reinheckel, Thomas
Mueller, Thomas D.
Bodem, Jochen
Lutz, Manfred B.
Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
title Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
title_full Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
title_fullStr Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
title_full_unstemmed Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
title_short Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
title_sort low doses of cholera toxin and its mediator camp induce ctla-2 secretion by dendritic cells to enhance regulatory t cell conversion
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536293/
https://www.ncbi.nlm.nih.gov/pubmed/28759565
http://dx.doi.org/10.1371/journal.pone.0178114
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