Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice.
Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice.
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DOI：
10.1038/ncomms10991
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发表时间：
2016-03-15
影响因子：
16.6
通讯作者：
Daniel C
中科院分区：
文献类型：
--
作者：
Serr I;Fürst RW;Achenbach P;Scherm MG;Gökmen F;Haupt F;Sedlmeier EM;Knopff A;Shultz L;Willis RA;Ziegler AG;Daniel C
免疫耐受部分是由Foxp3+调节性T(Treg)细胞执行的，它抑制自身反应性T细胞。在自身免疫性1型糖尿病(T1D)中，耐受性受损会促进产生胰岛素的β细胞的破坏。针对Foxp3+Treg诱导和预防患者胰岛自身免疫的自身抗原特异性疫苗策略的开发仍处于初级阶段。在这里，我们使用植入人造血干细胞的NSG-HL A-DQ8转基因小鼠，为体内诱导人类自身抗原特异性Foxp3+Treg提供了直接证据。我们鉴定了人类白细胞抗原DQ8限制的胰岛素特异的CD4+T细胞，并证明了在体内用强激动型胰岛素模拟表位亚免疫原性疫苗有效地诱导了人胰岛素特异的Foxp3+Treg。诱导的人Treg细胞稳定，表现为Foxp3、CTLA4、IL-2Rα和TIGIT等Treg标志性基因表达增加，并能有效抑制效应性T细胞。这种Foxp3+Treg诱导不会触发任何效应性T细胞。因此，这些T1D候选疫苗可能代表着对诱导人类Foxp3+Treg的挑战的权宜之计的改进，并开发新的精密药物来预防T1D风险儿童的胰岛自身免疫。1型糖尿病与胰腺中产生胰岛素的β细胞丧失自我耐受性有关。在这里，作者表明，胰岛素模拟表位免疫可以诱导人类胰岛素特异性调节性T细胞在人源化小鼠模型中介导耐受。
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.