title: Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice.
abstract: Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4(+)T cells and demonstrate efficient human insulin-specific Foxp3(+)Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Rα and TIGIT and can efficiently suppress effector T cells. Such Foxp3(+)Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3(+)Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D.
authors.affiliation: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Heidemannstrasse 1, 80939 München, Germany.|Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Serr
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.|Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, Heidemannstrasse 1, 80939 München, Germany.
authors.forename: Rainer W
authors.initials: RW
authors.lastname: Fürst
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.|Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, Heidemannstrasse 1, 80939 München, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Achenbach
authors.affiliation: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Heidemannstrasse 1, 80939 München, Germany.|Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Scherm
authors.affiliation: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Heidemannstrasse 1, 80939 München, Germany.|Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.
authors.forename: Füsun
authors.initials: F
authors.lastname: Gökmen
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.|Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, Heidemannstrasse 1, 80939 München, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Haupt
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.|Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, Heidemannstrasse 1, 80939 München, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Sedlmeier
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.|Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, Heidemannstrasse 1, 80939 München, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Knopff
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Shultz
authors.affiliation: Emory Vaccine Center, NIH Tetramer Core Facility, 201 Dowman Drive, Atlanta, Georgia 30322, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Willis
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.|Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, Heidemannstrasse 1, 80939 München, Germany.
authors.forename: Anette-Gabriele
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Heidemannstrasse 1, 80939 München, Germany.|Deutsches Zentrum für Diabetesforschung (DZD), Ingolstädter Landstrasse 1, 85764 München, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Daniel
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007328:Insulin / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014612:Vaccines / Q000276:immunology*; D055815:Young Adult
chemical_list: D001324:Autoantigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; C508018:Il2ra protein, mouse; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D011971:Receptors, Immunologic; C556305:T cell Ig and ITIM domain protein, mouse; D014612:Vaccines