title: A divergent population of autoantigen-responsive CD4+T cells in infants prior to β cell autoimmunity.
abstract: Autoimmune diabetes is marked by sensitization to β cell self-antigens in childhood. We longitudinally followed at-risk children from infancy and performed single-cell gene expression in β cell antigen-responsive CD4+T cells through pre- and established autoimmune phases. A striking divergence in the gene signature of β cell antigen-responsive naïve CD4+T cells from children who developed β cell autoimmunity was found in infancy, well before the appearance of β cell antigen-specific memory T cells or autoantibodies. The signature resembled a pre-T helper 1 (TH1)/TH17/T follicular helper cell response with expression ofCCR6,IL21,TBX21,TNF,RORC,EGR2,TGFB1, andICOS, in the absence ofFOXP3,IL17, and other cytokines. The cells transitioned to anIFNG-TH1 memory phenotype with the emergence of autoantibodies. We suggest that the divergent naïve T cell response is a consequence of genetic or environmental priming during unfavorable perinatal exposures and that the signature will guide future efforts to detect and prevent β cell autoimmunity.
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Anne-Kristin
authors.identifier: 0000-0003-3151-826X
authors.initials: AK
authors.lastname: Heninger
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Anne
authors.identifier: 0000-0001-8009-5959
authors.initials: A
authors.lastname: Eugster
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Kuehn
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, U.K.
authors.forename: Florian
authors.initials: F
authors.lastname: Buettner
authors.affiliation: Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Matthias
authors.identifier: 0000-0003-2868-5155
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Annett
authors.identifier: 0000-0002-2664-8994
authors.initials: A
authors.lastname: Lindner
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Sevina
authors.identifier: 0000-0001-8360-7868
authors.initials: S
authors.lastname: Dietz
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Sibille
authors.identifier: 0000-0002-7061-8928
authors.initials: S
authors.lastname: Jergens
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wilhelm
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Forschergruppe Diabetes e.V., Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyerlein
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Forschergruppe Diabetes e.V., Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany. ezio.bonifacio@crt-dresden.de.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.|Paul Langerhans Institute Dresden of the Helmholtz Centre Munich at the Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Institute for Diabetes and Obesity, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Ezio
authors.identifier: 0000-0002-8704-4713
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D020869:Gene Expression Profiling; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007223:Infant; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology*; D013744:Tetanus Toxin / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D013744:Tetanus Toxin; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2