title: Hypomethylation at the regulatory T cell-specific demethylated region in CD25hi T cells is decoupled from FOXP3 expression at the inflamed site in childhood arthritis.
abstract: The maintenance of FOXP3 expression in CD25(hi) regulatory T cells (Tregs) is crucial to the control of inflammation and essential for successful Treg transfer therapies. Coexpression of CD25 and FOXP3 in combination with a hypomethylated region within the FOXP3 gene, called the Treg-specific demethylated region (TSDR), is considered the hallmark of stable Tregs. The TSDR is an epigenetic motif that is important for stable FOXP3 expression and is used as a biomarker to measure Treg lineage commitment. In this study, we report that, unlike in peripheral blood, CD4(+) T cell expression of CD25 and FOXP3 is frequently dissociated at the inflamed site in patients with juvenile idiopathic arthritis, which led us to question the stability of human Tregs in chronic inflammatory environments. We describe a novel CD4(+)CD127(lo)CD25(hi) human T cell population that exhibits extensive TSDR and promoter demethylation in the absence of stable FOXP3 expression. This population expresses high levels of CTLA-4 and can suppress T conventional cell proliferation in vitro. These data collectively suggest that this population may represent a chronically activated FOXP3(lo) Treg population. We show that these cells have defects in IL-2 signaling and reduced expression of a deubiquitinase important for FOXP3 stability. Clinically, the proportions of these cells within the CD25(hi) T cell subset are increased in patients with the more severe courses of disease. Our study demonstrates, therefore, that hypomethylation at the TSDR can be decoupled from FOXP3 expression in human T cells and that environment-specific breakdown in FOXP3 stability may compromise the resolution of inflammation in juvenile idiopathic arthritis.
authors.affiliation: Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; and d.bending@ucl.ac.uk.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-0071-1163
authors.initials: D
authors.lastname: Bending
authors.affiliation: Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; and.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Pesenacker
authors.affiliation: Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; and.
authors.forename: Simona
authors.initials: S
authors.lastname: Ursu
authors.affiliation: Medical School, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Lom
authors.affiliation: Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; and.
authors.forename: Balathas
authors.initials: B
authors.lastname: Thirugnanabalan
authors.affiliation: Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; and.
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
mesh_terms: D000328:Adult; D001171:Arthritis, Juvenile / Q000276:immunology*; D015415:Biomarkers; D060908:CTLA-4 Antigen / Q000096:biosynthesis; D049109:Cell Proliferation; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis* / Q000737:chemistry; D008297:Male; D008745:Methylation; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D064570:Ubiquitin-Specific Proteases / Q000235:genetics
chemical_list: D015415:Biomarkers; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508717:IL17A protein, human; C508594:IL2 protein, human; C508017:IL2RA protein, human; D020381:Interleukin-17; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D064570:Ubiquitin-Specific Proteases
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