title: Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells.
abstract: Interest in manipulating the immunosuppressive powers of Foxp3-expressing T regulatory cells as an immunotherapy has been tempered by their reported ability to produce proinflammatory 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 TCR-stimulation in vitro in the presence of TGF-β. We show that iTreg cells can produce significant amounts of three proinflammatory 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 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.
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Ben C
authors.initials: BC
authors.lastname: Reynolds
authors.forename: Darryl G
authors.initials: DG
authors.lastname: Turner
authors.forename: Rhoanne C
authors.initials: RC
authors.lastname: McPherson
authors.forename: Catriona T
authors.initials: CT
authors.lastname: Prendergast
authors.forename: Richard G
authors.initials: RG
authors.lastname: Phelps
authors.forename: Neil A
authors.initials: NA
authors.lastname: Turner
authors.forename: Richard A
authors.initials: RA
authors.lastname: O'Connor
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C486767:Il27 protein, mouse; D007376:Interleukin-2; D015850:Interleukin-6; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Autoimmunity; Cytokines; Immunotherapy; Regulatory T cells; Treg cells