Induction of Potent CD8 T Cell Cytotoxicity by Specific Targeting of Antigen to Cross-Presenting Dendritic Cells In Vivo via Murine or Human XCR1
Induction of Potent CD8 T Cell Cytotoxicity by Specific Targeting of Antigen to Cross-Presenting Dendritic Cells In Vivo via Murine or Human XCR1
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DOI：
10.4049/jimmunol.1401903
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发表时间：
2015-02-01
影响因子：
4.4
通讯作者：
Kroczek, Richard A.
中科院分区：
文献类型：
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作者：
Hartung, Evelyn;Becker, Martina;Kroczek, Richard A.
目前的亚单位疫苗不能诱导防御某些感染和治疗肿瘤疾病所需的Ag特异性CD8（+）T细胞的细胞毒性。在实验疫苗中，可以通过将Ag靶向交叉呈递树突状细胞（DC）来引发细胞毒性应答，但是几乎所有可用的系统都使用也在其他细胞上表达的靶分子，因此缺乏所需的特异性。在目前的工作中，我们通过将Ag靶向XCR1诱导CD8（+）T细胞的细胞毒性，XCR1是一种仅在鼠和人交叉呈递DC上表达的趋化因子受体。用单克隆抗体或趋化因子配体XCL 1靶向Ag是高度特异性的，如用XCR 1缺陷小鼠所确定的。当与佐剂一起应用时，两种载体系统诱导有效的细胞毒性反应，防止接种的侵袭性肿瘤的生长。通过产生仅在其交叉呈递DC上表达人XCR 1的转基因小鼠，我们可以证明使用人XCL 1作为载体靶向Ag在体内是完全有效的。XCR1介导的Ag靶向交叉呈递DC的特异性和效率，加上其缺乏副作用，使该系统成为开发人类治疗性细胞毒性疫苗的主要候选者。
Current subunit vaccines are incapable of inducing Ag-specific CD8(+) T cell cytotoxicity needed for the defense of certain infections and for therapy of neoplastic diseases. In experimental vaccines, cytotoxic responses can be elicited by targeting of Ag into cross-presenting dendritic cells (DC), but almost all available systems use target molecules also expressed on other cells and thus lack the desired specificity. In the present work, we induced CD8(+) T cell cytotoxicity by targeting of Ag to XCR1, a chemokine receptor exclusively expressed on murine and human cross-presenting DC. Targeting of Ag with a mAb or the chemokine ligand XCL1 was highly specific, as determined with XCR1-deficient mice. When applied together with an adjuvant, both vector systems induced a potent cytotoxic response preventing the outgrowth of an inoculated aggressive tumor. By generating a transgenic mouse only expressing the human XCR1 on its cross-presenting DC, we could demonstrate that targeting of Ag using human XCL1 as vector is fully effective in vivo. The specificity and efficiency of XCR1-mediated Ag targeting to cross-presenting DC, combined with its lack of adverse effects, make this system a prime candidate for the development of therapeutic cytotoxic vaccines in humans.