Type 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice

Isabelle Serr, Rainer W. Fürst, Peter Achenbach, Martin G. Scherm, Füsun Gökmen, Florian Haupt, Eva-Maria Sedlmeier, Annette Knopff, Leonard Shultz, Richard A. Willis, Anette-Gabriele Ziegler and Carolin Daniel ()
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Isabelle Serr: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München
Rainer W. Fürst: Deutsches Zentrum für Diabetesforschung (DZD)
Peter Achenbach: Deutsches Zentrum für Diabetesforschung (DZD)
Martin G. Scherm: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München
Füsun Gökmen: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München
Florian Haupt: Deutsches Zentrum für Diabetesforschung (DZD)
Eva-Maria Sedlmeier: Deutsches Zentrum für Diabetesforschung (DZD)
Annette Knopff: Deutsches Zentrum für Diabetesforschung (DZD)
Leonard Shultz: The Jackson Laboratory
Richard A. Willis: Emory Vaccine Center, NIH Tetramer Core Facility
Anette-Gabriele Ziegler: Deutsches Zentrum für Diabetesforschung (DZD)
Carolin Daniel: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10991

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