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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

Please always quote using this URN: urn:nbn:de:bvb:20-opus-158244
  • 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 lymphocyteImmature 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.show moreshow less

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Metadaten
Author: 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
URN:urn:nbn:de:bvb:20-opus-158244
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Virologie und Immunbiologie
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Chemie und Pharmazie / Institut für Physikalische und Theoretische Chemie
Language:English
Parent Title (English):PLoS ONE
Year of Completion:2017
Volume:12
Issue:7
Pagenumber:e0178114
Source:PLoS ONE 12(7): e0178114 (2017). DOI: 10.1371/journal. pone.0178114
DOI:https://doi.org/10.1371/journal.pone.0178114
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:T cells; cell differentiation; cholera; cytokines; immune evasion; regulatory T cells; small interfering RNAs; toxins
Release Date:2018/03/22
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2017
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International