The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice
The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice
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DOI：
10.1172/jci37607
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发表时间：
2009-08-01
影响因子：
15.9
通讯作者：
Yang, Yiping
中科院分区：
文献类型：
--
作者：
Zhu, Jiangao;Huang, Xiaopei;Yang, Yiping
重组腺相关病毒（AAV）已广泛用于体内基因治疗。然而，对AAV的适应性免疫应答已经在AAV载体的临床应用中造成了显著的障碍。最近的进展表明，先天免疫在形成适应性免疫应答中起着至关重要的作用。AAV如何激活先天免疫，从而促进AAV靶向的适应性免疫应答，仍然是未知的。在这里，我们表明，AAV激活小鼠浆细胞样树突状细胞（pDC）通过TLR 9产生I型IFN。在体内，TLR 9-MyD 88途径对于活化CD 8（+）T细胞对转基因产物和AAV衣壳的应答是至关重要的，导致转基因表达的丧失和转基因产物特异性抗体和AAV中和抗体的产生。我们进一步证明了靶向AAV的适应性免疫的TLR 9依赖性激活是由I型IFN介导的，并且人pDC可以在体外被激活以通过TLR 9诱导I型IFN产生。这些结果揭示了TLR 9-MyD 88-I型IFN途径在诱导对AAV的适应性免疫应答中的重要作用，并表明干扰该途径的策略可以改善人类中AAV介导的基因治疗的结果。
Recombinant adeno-associated viruses (AAVs) have been used widely for in vivo gene therapy. However, adaptive immune responses to AAV have posed a significant hurdle in clinical application of AAV vectors. Recent advances have suggested a crucial role for innate immunity in shaping adaptive immune responses. How AAV activates innate immunity, and thereby promotes AAV-targeted adaptive immune responses, remains unknown. Here we show that AAV activates mouse plasmacytoid DCs (pDCs) via TLR9 to produce type I IFNs. In vivo, the TLR9-MyD88 pathway was crucial to the activation of CD8(+) T cell responses to both the transgene product and the AAV capsid, leading to loss of transgene expression and the generation of transgene product-specific and AAV-neutralizing antibodies. We further demonstrate that TLR9-dependent activation of adaptive immunity targeting AAV was mediated by type I IFNs and that human pDCs could be activated in vitro to induce type I IFN production via TLR9. These results reveal an essential role for the TLR9-MyD88-type I IFN pathway in induction of adaptive immune responses to AAV and suggest that strategies that interfere with this pathway may improve the outcome of AAV-mediated gene therapy in humans.