Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10991
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Funding
- Junior Research Group at Helmholtz Zentrum Munchen
- Deutsche Forschungsgemeinschaft [CRC1054]
- Juvenile Diabetes Research Foundation [JDRF 2-SRA-2014-161-Q-R, JDRF 17-2012-16, JDRF 6-2012-20]
- Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus) - Federal Ministry of Education and Research [FKZ 01GI0805-07, FKZ 01GI0805]
- German Center for Diabetes Research (DZD)
- National Institutes of Health [U01 DK089572]
- Helmsley Charitable Trust grant [2012PG-T1D018]
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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 beta-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-2R alpha and TIGIT and can efficiently suppress effector T cells. Such Foxp3(+)Treg-induction does not trigger any effector Tcells. 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.
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