Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity
Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity
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DOI：
10.4049/jimmunol.181.5.3422
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发表时间：
2008-09-01
影响因子：
4.4
通讯作者：
Noble, Alistair
中科院分区：
文献类型：
--
作者：
Wells, James W.;Cowled, Christopher J.;Noble, Alistair
消除恶性细胞和细胞内感染需要CTL和Th1炎症之间的合作。树突状细胞通过共刺激和细胞因子驱动这种反应。我们已经确定了在小鼠体内特定CD8(+)T细胞指数级扩增所需的关键信号。两种或两种以上TLR激动剂、抗CD40、干扰素-γ和表面活性物质的免疫足以推动CD8对肽或蛋白抗原的反应达到前所未有的水平，并高度极化Th1CD4反应。CD40信号是CD8扩增所必需的，但可以由伴随的CD4Th反应提供，而不是抗CD40。这些途径的触发激活了髓系树突状细胞和浆细胞样树突状细胞的迁移和激活以及IL-12的分泌。因此，交叉呈现可以被用来诱导对多肽/蛋白质AGS的强大的细胞毒反应和长期记忆。当与来自酪氨酸酶相关蛋白2的肿瘤相关肽结合时，我们的联合佐剂方法有效地阻止了体内黑色素瘤模型中的肿瘤生长，并且比抗CD40和单一TLR激动剂更有效。抗肿瘤免疫与天然处理和呈递的肿瘤抗原特异性的长寿效应记忆CD8细胞相关，肿瘤保护部分但不完全依赖于CD8T细胞。这种灵活的策略比现有的佐剂更有效，并为快速开发疫苗提供了技术平台。
Elimination of malignant cells and intracellular infections involves collaboration between CTLs and Th1 inflammation. Dendritic cells drive this response via costimulation and cytokines. We have defined key signals required for the exponential expansion of specific CD8(+) T cells in vivo in mice. Immunization with two or more TLR agonists, anti-CD40, IFN-gamma, and surfactant were sufficient to drive unprecedented levels of CD8 response to peptide or protein Ag and highly polarized Th1 CD4 responses. CD40 signaling was required for CD8 expansion but could be provided by a concomitant CD4 Th response in place of anti-CD40. Triggering of these pathways activated migration and activation of myeloid and plasmacytoid dendritic cells and secretion of IL-12. Cross-presentation can thus be exploited to induce potent cytotoxic responses and long-term memory to peptide/protein Ags. When combined with a tumor-associated peptide from tyrosinase-related protein 2, our combined adjuvant approach effectively halted tumor growth in an in vivo melanoma model and was more effective than anti-CD40 and a single TLR agonist. Antitumor immunity was associated with long-lived effector memory CD8 cells specific for the naturally processed and presented tumor Ag, and tumor protection was partially but not entirely dependent on CD8 T cells. This flexible strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development.