Type 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice
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 b 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 2Ra 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.
Nature communications