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: 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, Carolin Daniel
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 10991 (Mar 15 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 26975663 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Adolescent
• Adult
• Animals
• Autoantigens (immunology)
• Autoimmunity (immunology)
• CTLA-4 Antigen (genetics, immunology)
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1 (drug therapy, immunology)
• Female
• Forkhead Transcription Factors (genetics, 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, immunology)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Mice, Transgenic
• Receptors, Immunologic (genetics, immunology)
• Self Tolerance (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Vaccines (immunology)
• Young Adult