Open AccessLow doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
Author(s) -
Cinthia Silva-Vilches,
Katrien Pletinckx,
Miriam Lohnert,
Vladimir Pavlović,
DiyaaElDin Ashour,
Vini John,
Emilia Vendelova,
Susanne Kneitz,
Jie Zhou,
Rena Chen,
Thomas Reinheckel,
Thomas D. Mueller,
Jochen Bodem,
Manfred B. Lutz
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0178114
Subject(s) - foxp3 , microbiology and biotechnology , cholera toxin , ctla 4 , immune system , cytotoxic t cell , antigen presenting cell , t cell , antigen , biology , dendritic cell , chemistry , immunology , in vitro , biochemistry
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 .