Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity
Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity
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DOI：
10.1182/blood-2008-08-176446
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发表时间：
2009-04-30
期刊：
影响因子：
20.3
通讯作者：
Shimizu, Kanako
中科院分区：
文献类型：
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作者：
Fujii, Shin-ichiro;Goto, Akira;Shimizu, Kanako
树突状细胞（dc）在危险信号的原位成熟在先天免疫和适应性免疫的联系中起着核心作用。我们之前已经证明，通过给药α -半乳糖神经酰胺（α - galcer）负载的肿瘤细胞激活不变自然杀伤T （iNKT）细胞，可以在DC成熟过程中作为细胞佐剂。在本研究中，我们使用携带α - galcer并转染抗原编码mRNA的同种异体成纤维细胞，从而将inkt细胞活化的佐剂作用与抗原递送到体内DCs结合起来。我们发现这些细胞产生抗原蛋白并激活NK和iNKT细胞。当注射到主要组织相容性复合体（MHC）不匹配的小鼠中时，它们引发抗原特异性t细胞反应并提供肿瘤保护，这表明这些免疫反应依赖于宿主dc。此外，满载α - galcer的抗原表达成纤维细胞比那些表达NK细胞配体的成纤维细胞导致更有效的t细胞反应。因此，糖脂负载、mrna转染的同种异体成纤维细胞作为细胞载体，提供inkt细胞活化，导致DC成熟和t细胞免疫。通过利用先天免疫系统并对各种抗原产生适应性免疫反应，这种独特的工具可以证明在临床上有益于开发针对恶性和传染病的免疫疗法。(血。2009;113:4262 - 4272)
The maturation of dendritic cells (DCs) in situ by danger signals plays a central role in linking innate and adaptive immunity. We previously demonstrated that the activation of invariant natural killer T (iNKT) cells by administration of alpha-galactosylceramide (alpha-GalCer)-loaded tumor cells can act as a cellular adjuvant through the DC maturation. In the current study, we used allogeneic fibroblasts loaded with alpha-GalCer and transfected with antigen-encoding mRNA, thus combining the adjuvant effects of iNKT-cell activation with delivery of antigen to DCs in vivo. We found that these cells produce antigen protein and activate NK and iNKT cells. When injected into major histocompatibility complex (MHC)-mismatched mice, they elicited antigen-specific T-cell responses and provided tumor protection, suggesting that these immune responses depend on host DCs. In addition, antigen-expressing fibroblasts loaded with alpha-GalCer lead to a more potent T-cell response than those expressing NK cell ligands. Thus, glycolipid-loaded, mRNA-transfected allogeneic fibroblasts act as cellular vectors to provide iNKT-cell activation, leading to DC maturation and T-cell immunity. By harnessing the innate immune system and generating an adaptive immune response to a variety of antigens, this unique tool could prove clinically beneficial in the development of immunotherapies against malignant and infectious diseases. (Blood. 2009;113:4262-4272)