Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells
Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells
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DOI：
10.1016/j.ymthe.2019.11.011
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发表时间：
2020-03-04
影响因子：
12.4
通讯作者：
Herzog, Roland W.
中科院分区：
文献类型：
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作者：
Shirley, Jamie L.;Keeler, Geoffrey D.;Herzog, Roland W.
腺相关病毒（AAV）载体被广泛应用于临床基因治疗中，通过体内基因转移来纠正遗传性疾病。虽然这些载体是有用的，部分原因是它们的免疫原性有限，但针对载体成分的免疫反应在人类中的应用非常复杂。这些包括，例如，通过浆细胞样树突状细胞（pDCs）对载体成分的先天免疫感知，它通过toll样受体9感知载体DNA基因组。适应性免疫反应采用传统树突状细胞（cDCs）的抗原呈递，导致衣壳特异性CD8+ T细胞的交叉启动。在这项研究中，我们试图确定促进CD8+ T细胞活化所必需的CD8+ T细胞许可的机制。单克隆抗体治疗阻断1型干扰素（T1 IFN）信号传导可阻止交叉启动。此外，在细胞类型受限的敲除小鼠中进行的实验显示，cdc对T1 IFN （IFNaR）受体有特异性需求。相比之下，自然杀伤细胞（NK）是不需要的，这表明T1 IFN对cdc的影响是直接的而不是间接的。此外，交叉启动需要CD4(+) T细胞通过CD40-CD40L进行共刺激，阻断共刺激而不阻断T1 IFN也会减少针对衣壳的抗体形成。这些机制的见解为靶向免疫干预的发展提供了信息。
Adeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses employ antigen presentation by conventional dendritic cells (cDCs), which leads to cross-priming of capsid-specific CD8+ T cells. In this study, we sought to determine the mechanisms that promote licensing of cDCs, which is requisite for CD8+ T cell activation. Blockage of type 1 interferon (T1 IFN) signaling by monoclonal antibody therapy prevented cross-priming. Furthermore, experiments in cell-type-restricted knockout mice showed a specific requirement for the receptor for T1 IFN (IFNaR) in cDCs. In contrast, natural killer (NK) cells are not needed, indicating a direct rather than indirect effect of T1 IFN on cDCs. In addition, co-stimulation by CD4(+) T cells via CD40-CD40L was required for cross-priming, and blockage of co-stimulation but not of T1 IFN additionally reduced antibody formation against capsid. These mechanistic insights inform the development of targeted immune interventions.