Flores-Langarica Adriana, Bobat Saeeda, Marshall Jennifer L, Yam-Puc Juan Carlos, Cook Charlotte N, Serre Karine, Kingsley Robert A, Flores-Romo Leopoldo, Uematsu Satoshi, Akira Shizuo, Henderson Ian R, Toellner Kai M, Cunningham Adam F
Division of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
Deparamento de Biologia Celular. CINVESTAV. Mexico, D.F. Mexico.
Eur J Immunol. 2015 Aug;45(8):2299-311. doi: 10.1002/eji.201545564. Epub 2015 Jun 24.
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.
鼠伤寒沙门氏菌（STm）的可溶性鞭毛蛋白（sFliC）可通过Toll样受体5（TLR5）的连接诱导自身以及共给药抗原产生Th2反应。这些特性表明，如果同时给予两种抗原，sFliC可能会调节对Th1抗原（如活的STm）的反应。用sFliC和STm共同免疫小鼠后，与单独使用STm相比，Th1 T细胞（T-bet(+) IFN-γ(+) CD4 T细胞）数量减少，且STm的清除受损。相比之下，对STm的早期滤泡外B细胞反应没有明显缺陷。这些效应依赖于TLR5以及STm的鞭毛蛋白表达。这些效应的机制与sFliC诱导产生的白细胞介素-4无关，而是与sFliC共同免疫对树突状细胞（DCs）的影响有关。用STm和sFliC共同免疫后，脾脏DCs共刺激分子的表达较低，且白细胞介素-12和肿瘤坏死因子α的表达动力学发生了深刻改变。使用体内预处理的DCs进行的体外实验证实，sFliC的效应是由于在DCs与初始T细胞协调相互作用的关键窗口期DC功能发生了改变。这对于理解在感染诱导的Th1介导的炎症过程中如何实现Th1启动的限制具有重要意义。
