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

Ben C. Reynolds, Darryl G. Turner, Rhoanne C. McPherson, Catriona T. Prendergast, Richard G. Phelps, Neil A. Turner, Richard A. O'Connor, Stephen M. Anderton

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)3342–3352
JournalEuropean Journal of Immunology
Volume44
Issue number11
Early online date1 Oct 2014
DOIs
Publication statusPublished - 14 Nov 2014

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