Caveolin-1-Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization
Caveolin-1-Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization
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DOI：
10.4049/jimmunol.1102828
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发表时间：
2012-09-15
影响因子：
4.4
通讯作者：
Wang, Bin
中科院分区：
文献类型：
--
作者：
Li, Jinyao;Geng, Shuang;Wang, Bin
通过疫苗接种诱导抗原特异性调节性T细胞(ITregs)是治疗自身免疫性疾病的一种有前途的策略。我们先前证明，DNA和蛋白质联合免疫通过诱导CD11c(+)、CD40(Low)、IL-10(+)调节性树突状细胞(DCregs)，将初始T细胞转化为抗原特异性的iTregs。然而，目前尚不清楚联合免疫是如何诱导DCregs的。在本文中，我们报道了这一事件是由序列匹配的DNA和蛋白质免疫原通过小窝介导的内吞作用共同进入同一DC而启动的，这导致小窝的主要成分小窝蛋白-1(Cav-1)的磷酸化被抑制，并上调了Tollip。这触发了下游信号，上调了细胞因子信号1的抑制物，下调了核因子-kappaB和STAT-1α的表达。沉默Cav-1或Tollip可阻断负性信号转导，导致CD40表达上调，IL-10表达下调，iTreg诱导功能丧失。我们进一步证明，通过给予序列匹配的DNA和蛋白质免疫原，可以在原代DC和JAWS II DC系的培养中诱导DCregs。体外产生的DCregs在改善几种小鼠模型的自身免疫性和炎症性疾病方面是有效的。因此，我们的研究表明，DNA和蛋白质共免疫通过Cav-1和Tollip介导的负信号诱导DCregs。它还描述了一种在体外产生治疗性DCregs的新方法。免疫学杂志，2012,189：2852-2859。
Induction of Ag-specific regulatory T cells (iTregs) by vaccination is a promising strategy for treating autoimmune diseases. We previously demonstrated that DNA and protein covaccination converted naive T cells to Ag-specific iTregs by inducing CD11c(+) CD40(low)IL-10(+) regulatory dendritic cells (DCregs). However, it is unclear how coimmunization induces the DCregs. In this paper, we report that the event is initiated by coentry of sequence-matched DNA and protein immunogens into the same DC via caveolae-mediated endocytosis, which leads to inhibition of phosphorylation of caveolin-1 (Cav-1), the main component of caveolae, and upregulation of Tollip. This triggers downstream signaling that upregulates suppressor of cytokine signaling 1 and downregulates NF-kappa B and STAT-1 alpha. Silencing either Cav-1 or Tollip blocks the negative signaling, leading to upregulated expression of CD40, downregulated production of IL-10, and loss of iTreg-inducing function. We further show that DCregs can be induced in culture from primary DCs and JAWS II DC lines by feeding them sequence-matched DNA and protein immunogens. The in vitro-generated DCregs are effective in ameliorating autoimmune and inflammatory diseases in several mouse models. Our study thus suggests that DNA and protein coimmunization induces DCregs through Cav-1- and Tollip-mediated negative signaling. It also describes a novel method for generating therapeutic DCregs in vitro. The Journal of Immunology, 2012, 189: 2852-2859.