Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production.
Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production.
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DOI：
10.1002/eji.201545564
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发表时间：
2015-08
影响因子：
5.4
通讯作者：
Cunningham AF
中科院分区：
文献类型：
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作者：
Flores-Langarica A;Bobat S;Marshall JL;Yam-Puc JC;Cook CN;Serre K;Kingsley RA;Flores-Romo L;Uematsu S;Akira S;Henderson IR;Toellner KM;Cunningham AF
来自鼠伤寒沙门氏菌（STm）的可溶性鞭毛蛋白（sFliC）可以通过连接TLR 5诱导对自身和共同施用的抗原的Th 2应答。这些性质表明，如果同时给予两种抗原，sFliC可以潜在地调节对Th 1抗原的应答，如活STm。在用sFliC和STm共免疫小鼠后，与单独的STm相比，Th 1 T细胞（T-bet +IFN-γ+ CD 4 T细胞）减少，并且STm的清除受损。相比之下，早期滤泡外B细胞对STm的反应没有明显缺陷。这些作用依赖于STm的TLR 5和鞭毛蛋白表达。这些作用的机制与sFliC诱导的IL-4无关，而是与sFliC共免疫对DC的作用有关。在用STm和sFliC共免疫后，脾DC具有较低的共刺激分子表达，并显著改变了IL-12和TNFα表达的动力学。使用体内条件化DC的离体实验证实sFliC的作用是由于在DC和幼稚T细胞之间协调相互作用的关键窗口期间改变的DC功能。这对于理解在感染诱导的Th 1介导的炎症期间如何实现Th 1启动的限制具有显著意义。
Soluble flagellin (sFliC) from Salmonella Typhimurium (STm) can induce a Th2 response to itself and coadministered antigens through ligation of TLR5. These properties suggest that sFliC could potentially modulate responses to Th1 antigens like live STm if both antigens are given concurrently. After coimmunization of mice with sFliC and STm there was a reduction in Th1 T cells (T‐bet+IFN‐γ+ CD4 T cells) compared to STm alone and there was impaired clearance of STm. In contrast, there was no significant defect in the early extrafollicular B‐cell response to STm. These effects are dependent upon TLR5 and flagellin expression by STm. The mechanism for these effects is not related to IL‐4 induced to sFliC but rather to the effects of sFliC coimmunization on DCs. After coimmunization with STm and sFliC, splenic DCs had a lower expression of costimulatory molecules and profoundly altered kinetics of IL‐12 and TNFα expression. Ex vivo experiments using in vivo conditioned DCs confirmed the effects of sFliC were due to altered DC function during a critical window in the coordinated interplay between DCs and naïve T cells. This has marked implications for understanding how limits in Th1 priming can be achieved during infection‐induced, Th1‐mediated inflammation.