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腺病毒工程化的人树突状细胞通过 CXCL8/IL-8 和 CXCL10/IP-10 诱导自然杀伤细胞趋化。

Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10.

机构信息

University of Pittsburgh Cancer Institute; Pittsburgh, PA USA ; Deparment of Medicine; University of Pittsburgh School of Medicine; University of Pittsburgh; Pittsburgh, PA USA.

出版信息

Oncoimmunology. 2012 Jul 1;1(4):448-457. doi: 10.4161/onci.19788.

DOI:10.4161/onci.19788
PMID:22754763
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3382881/
Abstract

Recombinant adenovirus-engineered dendritic cells (Ad.DC) are potent vaccines for induction of anti-viral and anti-cancer T cell immunity. The effectiveness of Ad.DC vaccines may depend on the newly described ability of Ad.DC to crosstalk with natural killer (NK) cells via cell-to-cell contact, and to mediate activation, polarization and bridging of innate and adaptive immunity. For this interaction to occur in vivo, Ad.DC must be able to attract NK cells from surrounding tissues or peripheral blood. We developed a novel live mouse imaging system-based NK-cell migration test, and demonstrated for the first time that human Ad.DC induced directional migration of human NK cells across subcutaneous tissues, indicating that Ad.DC-NK cell contact and interaction could occur in vivo. We examined the mechanism of Ad.DC-induced migration of NK cells in vitro and in vivo. Ad.DC produced multiple chemokines previously reported to recruit NK cells, including immunoregulatory CXCL10/IP-10 and proinflammatory CXCL8/IL-8. In vitro chemotaxis experiments utilizing neutralizing antibodies and recombinant human chemokines showed that CXCL10/IP-10 and CXCL8/IL-8 were critical for Ad.DC-mediated recruitment of CD56(hi)CD16(-) and CD56(lo)CD16(+) NK cells, respectively. The importance of CXCL8/IL-8 was further demonstrated in vivo. Pretreatment of mice with the neutralizing anti-CXCL8/IL-8 antibody led to significant inhibition of Ad.DC-induced migration of NK cells in vivo. These data show that Ad.DC can recruit spatially distant NK cells toward a vaccine site via specific chemokines. Therefore, an Ad.DC vaccine can likely induce interaction with endogenous NK cells via transmembrane mediators, and consequently mediate Th1 polarization and amplification of immune functions in vivo.

摘要

重组腺病毒工程化树突状细胞（Ad.DC）是诱导抗病毒和抗癌 T 细胞免疫的有效疫苗。Ad.DC 疫苗的有效性可能取决于 Ad.DC 通过细胞间接触与自然杀伤 (NK) 细胞交叉对话的新能力，以及介导先天和适应性免疫的激活、极化和桥接。为了使这种相互作用在体内发生，Ad.DC 必须能够从周围组织或外周血中吸引 NK 细胞。我们开发了一种新的基于活鼠成像系统的 NK 细胞迁移测试，并首次证明人 Ad.DC 诱导人 NK 细胞穿过皮下组织的定向迁移，表明 Ad.DC-NK 细胞接触和相互作用可能在体内发生。我们研究了 Ad.DC 诱导 NK 细胞迁移的体内外机制。Ad.DC 产生了多种先前报道招募 NK 细胞的趋化因子，包括免疫调节趋化因子 CXCL10/IP-10 和促炎趋化因子 CXCL8/IL-8。利用中和抗体和重组人趋化因子的体外趋化实验表明，CXCL10/IP-10 和 CXCL8/IL-8 分别是 Ad.DC 介导招募 CD56(hi)CD16(-)和 CD56(lo)CD16(+) NK 细胞所必需的。在体内进一步证明了 CXCL8/IL-8 的重要性。用中和抗 CXCL8/IL-8 抗体预处理小鼠，导致体内 Ad.DC 诱导的 NK 细胞迁移显著抑制。这些数据表明，Ad.DC 可以通过特定趋化因子将空间上遥远的 NK 细胞募集到疫苗部位。因此，Ad.DC 疫苗可能通过跨膜介质诱导与内源性 NK 细胞的相互作用，并因此在体内介导 Th1 极化和免疫功能的放大。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/3382881/51373a5eb60b/onci-1-448-g6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/3382881/51373a5eb60b/onci-1-448-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/3382881/87634b2be73a/onci-1-448-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/3382881/8fef549e8c5c/onci-1-448-g2.jpg
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