title: Human IL-6RhiTIGIT-CD4+CD127lowCD25+T cells display potent in vitro suppressive capacity and a distinct Th17 profile.
abstract: To date many clinical studies aim to increase the number and/or fitness of CD4+CD127lowCD25+regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4+CD127lowCD25+TIGIT-T cells distinguished by their elevated IL-6R expression that lacked expression of HELIOS, showed higher CTLA-4 expression, and displayed increased suppressive capacity compared to IL-6RhiTIGIT+Tregs. IL-6RhiTIGIT-CD127lowCD25+T cells contained a majority of cells demethylated at FOXP3 and displayed a Th17 transcriptional signature, including RORC (RORγt) and the capacity of producing both pro- and anti-inflammatory cytokines, such as IL-17, IL-22 and IL-10. We propose that in vivo, in the presence of IL-6-associated inflammation, the suppressive function of CD4+CD127lowCD25+FOXP3+IL-6RhiTIGIT-T cells is temporarily disarmed allowing further activation of the effector functions and potential pathogenic tissue damage.
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Electronic address: ricardo.ferreira@well.ox.ac.uk.
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rainbow
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Arcadio
authors.initials: A
authors.lastname: Rubio García
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Marcin L
authors.initials: ML
authors.lastname: Pekalski
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Linsey
authors.initials: L
authors.lastname: Porter
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: João J
authors.initials: JJ
authors.lastname: Oliveira
authors.affiliation: Experimental Medicine and Immunotherapeutics, Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK; NIHR Cambridge Clinical Trial Unit, Cambridge NHS University Hospitals Trust, Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Waldron-Lynch
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Electronic address: john.todd@well.ox.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011971:Receptors, Immunologic / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human