RRC ID 67206
Author Serr I, Fürst RW, Achenbach P, Scherm MG, Gökmen F, Haupt F, Sedlmeier EM, Knopff A, Shultz L, Willis RA, Ziegler AG, Daniel C.
Title Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice.
Journal Nat Commun
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.
Volume 7
Pages 10991
Published 2016-3-15
DOI 10.1038/ncomms10991
PII ncomms10991
PMID 26975663
PMC PMC4796321
MeSH 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
IF 12.121
Human and Animal Cells HEV0110