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Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells

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    Rights statement: © 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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http://doi.wiley.com/10.1002/eji.201444687
Original languageEnglish
Pages (from-to)3342–3352
JournalEuropean Journal of Immunology
Volume44
Issue number11
Early online date1 Oct 2014
DOIs
Publication statusPublished - Nov 2014

Abstract

Interest in manipulating the immunosuppressive powers of Foxp3-expressing T regulatory (Treg) cells as an immunotherapy has been tempered by their reported ability to produce pro-inflammatory cytokines when manipulated in vitro, or in vivo. Understanding processes that can limit this potentially deleterious effect of Treg cells in a therapeutic setting is therefore important. Here we have studied this using induced (i)Treg cells in which de novo Foxp3 expression is driven by T-cell receptor (TCR)-stimulation in vitro in the presence of TGF-β. We show that iTreg cells can produce significant amounts of three pro-inflammatory cytokines (IFN-γ GM-CSF and TNF-α) upon secondary TCR stimulation. GM-CSF is a critical T-cell-derived cytokine for the induction of experimental autoimmune encephalomyelitis (EAE) in mice. Despite their apparent capacity to produce GM-CSF, myelin autoantigen-responsive iTreg cells were unable to provoke EAE. Instead, they maintained strong suppressive function in vivo, preventing EAE induction by their CD4+Foxp3− counterparts. We identified that although iTreg cells maintained the ability to produce IFN-γ and TNF-α in vivo, their ability to produce GM-CSF was selectively degraded upon antigen stimulation under inflammatory conditions. Furthermore we show that IL-6 and IL-27 individually, or IL-2 and TGF-β in combination, can mediate the selective loss of GM-CSF production by iTreg cells.

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