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PLoS One. 2017 Jul 31;12(7):e0178114. doi: 10.1371/journal.pone.0178114. eCollection 2017.

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

Author information

1
Institute of Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
2
Department of Physiological Chemistry, University of Wuerzburg, Wuerzburg, Germany.
3
BioLegend Inc., San Diego, California, United States of America.
4
Institute of Molecular Medicine and Cell Research, and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
5
Department of Molecular Plant Physiology and Biophysics, University of Wuerzburg, Wuerzburg, Germany.

Abstract

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.

PMID:
28759565
PMCID:
PMC5536293
DOI:
10.1371/journal.pone.0178114
[Indexed for MEDLINE]
Free PMC Article

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