Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8+ T cell response: A comparative study
Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8+ T cell response: A comparative study
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DOI：
10.1016/j.jconrel.2014.07.040
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发表时间：
2014-10-28
影响因子：
10.8
通讯作者：
Ossendorp, Ferry
中科院分区：
文献类型：
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作者：
Cruz, Luis J.;Rosalia, Rodney A.;Ossendorp, Ferry
在这里，我们证明了将抗原（Ag）靶向树突状细胞（DC）受体以实现有效的细胞毒性T细胞应答的重要性，该细胞毒性T细胞应答与DC的强烈活化相关。聚乙二醇化的聚乳酸-羟基乙酸共聚物（PLGA）纳米粒（NPs）被用来封装卵清蛋白（OVA）作为模型银。然后将该PLGA复合物与Toll样受体（TLR）3和7配体一起靶向不同的DC细胞表面分子。这些细胞表面分子，包括CD 40（TNF-α家族受体）、DEC-205（C型凝集素受体）和CD 11 c（整联蛋白受体），通过与NP偶联的特异性单克隆抗体（mAb）靶向。研究了这些不同的靶向策略激活DC并引发有效的CD 8（+）T细胞应答的效率。与对照非靶向NP相比，PLGA-（Ag/TLR 3 + 7 L）NP在体外更有效地靶向DC并被DC内化。我们观察到与DEC-205或CD 11 c靶向NP相比，CD 40靶向NP的内化小但显著改善。与非靶向NP相反，所有靶向NP同等地刺激DC产生IL-12和表达共刺激分子，诱导体外T细胞的强增殖和IFN-γ产生。此外，皮下接种CD 40、DEC-205和CD 11 c靶向NP在刺激CD 8 + T细胞应答方面始终显示出比非靶向NP更高的功效。然而，所有靶向NP疫苗显示出相同的引发细胞毒性CD 8 + T细胞的能力，其随后能够诱导靶向细胞裂解。总之，与NP至DC的非特异性递送相比，通过经由细胞表面分子靶向将NP疫苗递送至DC导致疫苗效力的强烈增强和T细胞应答的诱导。(C)2014爱思唯尔有限公司版权所有。
Here we demonstrated the importance of targeting antigens (Ags) to dendritic cell (DC) receptors to achieve an efficient cytotoxic T cell response which was associated with a strong activation of DC. Pegylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used to encapsulate ovalbumin (OVA) as a model Ag. This PLGA complex, together with Toll like receptor (TLR) 3 and 7 ligands, was then targeted to distinct DC cell-surface molecules. These cell-surface molecules, including CD40, a TNF-alpha family receptor, DEC-205, a C-type lectin receptor and CD11c, an integrin receptor, were targeted by means of specific monoclonal antibodies (mAbs) coupled to the NP. The efficiency of these different targeting strategies to activate DC and elicit a potent CD8(+) T cell response was studied. PLGA-(Ag/TLR3 + 7L) NP was more efficiently targeted to and internalized by DC in vitro compared to the control non-targeted NP. We observed a small but significantly improved internalization of CD40-targeted NP compared to DEC-205 or CD11c targeted NP. In contrast to non-targeted NP, all targeted NPs equally stimulated IL-12 production and expression of co-stimulatory molecules by DC, inducing strong proliferation and IFN-y production by T cells in vitro. Moreover, subcutaneous vaccination with CD40, DEC-205 and CD11c-targeted NP consistently showed higher efficacy than non-targeted NP in stimulating CD8+ T cell responses. However, all targeted NP vaccines showed an equal capacity to prime cytotoxic CD8+ T cells, which subsequently were able to induce targeted cell lysis. In conclusion, delivery of NP-vaccines to DC by targeting via cell-surface molecules leads to strong enhancement of vaccine potency and induction of T cell responses compared to non-specific delivery of NP to DC. (C) 2014 Elsevier B.V. All rights reserved.