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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 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.
Type 1 diabetes is associated with the loss of self-tolerance to the insulin-producing β-cells in the pancreas. Here the authors show that vaccination with insulin mimetopes can induce human insulin-specific regulatory T cells to mediate tolerance in a humanized mouse model.