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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 costimul...

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Main Authors: Silva-Vilches, Cinthia (Author) , Pletinckx, Katrien (Author) , Lohnert, Miriam (Author) , Pavlovic, Vladimir (Author) , Ashour, Diyaaeldin (Author) , John, Vini (Author) , Vendelova, Emilia (Author) , Kneitz, Susanne (Author) , Zhou, Jie (Author) , Chen, Rena (Author) , Reinheckel, Thomas (Author) , Müller, Thomas (Author) , Bodem, Jochen (Author) , Lutz, Manfred B. (Author)
Format: Article (Journal)
Language:English
Published: July 31, 2017
In: PLOS ONE
Year: 2017, Volume: 12, Issue: 7, Pages: e0178114
ISSN:1932-6203
DOI:10.1371/journal.pone.0178114
Online Access:Verlag, Volltext: https://doi.org/10.1371/journal.pone.0178114
Verlag, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178114
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Author Notes:Cinthia Silva-Vilches, Katrien Pletinckx, Miriam Lohnert, Vladimir Pavlovic, Diyaaeldin Ashour, Vini John, Emilia Vendelova, Susanne Kneitz, Jie Zhou, Rena Chen, Thomas Reinheckel, Thomas D. Mueller, Jochen Bodem, Manfred B. Lutz
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Summary: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 (CThi, CTlo) 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 CThi conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- 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 CTlo- 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.
Item Description:Gesehen am 19.08.2019
Physical Description:Online Resource
ISSN:1932-6203
DOI:10.1371/journal.pone.0178114

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