Toll-Like Receptor 6 Drives Differentiation of Tolerogenic Dendritic Cells and Contributes to LcrV-Mediated Plague Pathogenesis
Toll-Like Receptor 6 Drives Differentiation of Tolerogenic Dendritic Cells and Contributes to LcrV-Mediated Plague Pathogenesis
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DOI：
10.1016/j.chom.2008.09.004
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发表时间：
2008-10-16
影响因子：
30.3
通讯作者：
Jabri, Bana
中科院分区：
文献类型：
--
作者：
DePaolo, R. William;Tang, Fangming;Jabri, Bana
教育树突状细胞 (DC) 成为耐受性 DC，促进调节性 IL-10 免疫反应，代表了病原体的有效免疫逃避策略。据报道，鼠疫耶尔森氏菌毒力因子 LcrV 通过与 Toll 样受体 (TLR) 2 相互作用诱导 IL-10 产生。然而，TLR2(-/-) 小鼠无法免受皮下鼠疫感染。使用互补的体外和体内方法以及 LcrV 作为模型，我们证明 TLR6 与 TLR2 结合诱导耐受性 DC 和调节性 1 型 T 细胞选择性分泌 IL-10。相反，TLR1 与 TLR2 异二聚化，促进促炎性 IL-12p40 细胞因子，产生 DC 和炎性 T 细胞分化。 LcrV 特异性劫持 TLR2/6 通路来刺激 IL-10 的产生，从而阻止宿主的保护性炎症反应。这些结果解释了为什么 TLR2 可以介导促炎和抗炎反应，并将 TLR6 鉴定为驱动调节性 IL-10 反应的独特受体。
Educating dendritic cells (DC) to become tolerogenic DC, which promote regulatory IL-10 immune responses, represents an effective immune evasion strategy for pathogens. Yersinia pestis virulence factor LcrV is reported to induce IL-10 production via interaction with Toll-like receptor (TLR) 2. However, TLR2(-/-) mice are not protected against subcutaneous plague infection. Using complementary in vitro and in vivo approaches and LcrV as a model, we show that TLR6 associates with TLR2 to induce tolerogenic DC and regulatory type-1 T cells selectively secreting IL-10. In contrast, TLR1 heterodimerizes with TLR2 to promote proinflammatory IL-12p40 cytokine, producing DC and inflammatory T cell differentiation. LcrV specifically hijacks the TLR2/6 pathway to stimulate IL-10 production, which blocks host protective inflammatory responses. These results explain why TLR2 can mediate both pro- and anti-inflammatory responses and identify TLR6 as a distinct receptor driving regulatory IL-10 responses.