TLR ligand-induced type IIFNs affect thymopoiesis
TLR ligand-induced type IIFNs affect thymopoiesis
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DOI：
10.4049/jimmunol.180.11.7134
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Sekaly, Rafick-Pierre
中科院分区：
文献类型：
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作者：
Baron, Marie-Laurence;Gauchat, Dominique;Sekaly, Rafick-Pierre
TLRs与其配体之间的相互作用具有深刻的免疫调节特性。人们的注意力主要集中在TLR配体在病毒感染时对外周固有免疫和获得性免疫的影响上，而TLR激活对胸腺发育的影响很少。在这里，我们展示了用TLR3或TLR7配体处理小鼠胎儿胸腺器官培养(FTOCs)后，诱导了干扰素-α和-βmRNA的快速表达，这是急性和慢性病毒感染的标志。这导致早期发育受阻，细胞凋亡频率增加，胸腺细胞增殖减少，导致细胞密度立即下降。感染水泡性口炎病毒的FTOC，已知通过TLR7发挥作用，也受到类似的影响。在TLR配体或干扰素处理的FTOCs中，IL-7Rα链表达下调，细胞因子信号转导抑制因子1表达增加，转录调节因子独立性1表达降低。这表明这些途径在观察到的胸腺细胞发育变化中发挥了作用。综上所述，我们的数据表明TLR的激活和随后的I型干扰素的产生对T细胞的发育产生了有害的影响。由于TLR配体被广泛用作疫苗佐剂，我们的结果表明，它们的免疫调节作用主要由干扰素-α介导，因此应该考虑它们的免疫调节作用。
The interactions between TLRs and their ligands have profound immune modulation properties. Attention has focused mostly on the impact of TLR ligands on peripheral innate and adaptive immunity during viral infections, whereas little impact of TLR activation has been shown on thymic development. Here we show that treatment of murine fetal thymic organ cultures (FTOCs) with TLR3 or TLR7 ligands induced rapid expression of IFN-alpha and -beta mRNA, hallmarks of acute and chronic viral infections. This resulted in an early developmental blockade, increased frequencies of apoptotic cells, and decreased proliferation of thymocytes, which led to an immediate decrease in cellularity. FTOCs infected with vesicular stomatitis virus, known to act through TLR7, were similarly affected. Down-regulation of IL-7R alpha-chain expression, together with an increased expression of suppressor of cytokine signaling-1 and a concomitant decreased expression of the transcriptional regulator growth factor independence 1 were observed in TLR ligands or IFN-treated FTOCs. This indicates a role for these pathways in the observed changes in thymocyte development. Taken together, our data demonstrate that TLR activation and ensuing type I IFN production exert a deleterious effect on T cell development. Because TLR ligands are widely used as vaccine adjuvants, their immunomodulatory actions mediated mainly by IFN-alpha suggested by our results should be taken in consideration.