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

Nat Commun. 2016 Mar 15;7:10991. doi: 10.1038/ncomms10991.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Autoantigens / immunology
  • Autoimmunity / immunology
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Gene Expression Regulation / immunology*
  • HLA-DQ Antigens / genetics
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Immune Tolerance / immunology
  • Insulin / immunology*
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Transgenic
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Self Tolerance / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Vaccines / immunology*
  • Young Adult

Substances

  • Autoantigens
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Il2ra protein, mouse
  • Insulin
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Immunologic
  • T cell Ig and ITIM domain protein, mouse
  • Vaccines