Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists
Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists
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DOI：
10.1182/blood-2009-08-238543
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发表时间：
2010-03-11
期刊：
影响因子：
20.3
通讯作者：
Diebold, Sandra S.
中科院分区：
文献类型：
--
作者：
Rajagopal, Deepa;Paturel, Carine;Diebold, Sandra S.
对于诱导细胞毒性T淋巴细胞的佐剂的开发有很高的需求，这对于消除细胞内病原体和肿瘤细胞至关重要。Toll样受体（TLR）激动剂是实现这一作用的主要候选者，因为它们诱导先天免疫激活并促进适应性免疫应答。TLR 7激动剂R837在基底细胞癌治疗中的成功应用显示了在肿瘤免疫治疗中利用该途径的潜力。咪唑喹啉类如R837和刺激性ssRNA寡核苷酸都触发TLR 7介导的免疫激活，但关于它们促进免疫诱导的比较能力知之甚少。我们研究了咪唑并喹啉R848和ssRNA TLR 7激动剂polyUs 21之间先天免疫激活和佐剂活性的差异。与R848相反，polyUs 21在浆细胞样树突状细胞（PDCs）中诱导可检测水平的细胞内干扰素-α（IFN-α）。在免疫研究中，只有polyUs 21导致1型T辅助细胞和细胞毒性T淋巴细胞的强烈引发，并且它在诱导抗肿瘤免疫方面比R848更有效。值得注意的是，外源性IFN-α增强了R848的佐剂活性，而PDC的消耗消除了polyUs 21的佐剂性。因此，本研究确定PDC产生足够的IFN-α是疫苗效力的重要决定因素。（血。2010; 115：1949-1957）
There is a high demand for the development of adjuvants that induce cytotoxic T lymphocytes, which are crucial for the elimination of intracellular pathogens and tumor cells. Toll-like receptor (TLR) agonists are prime candidates to fulfill this role because they induce innate immune activation and promote adaptive immune responses. The successful application of the TLR7 agonist R837 for treatment of basal cell carcinoma shows the potential for exploiting this pathway in tumor immunotherapy. Imidazoquinolines like R837 and stimulatory ssRNA oligonucleotides both trigger TLR7-mediated immune activation, but little is known about their comparative ability to promote immunity induction. We investigated differences in innate immune activation and adjuvant activity between the imidazoquinoline R848 and the ssRNA TLR7 agonist polyUs21. In contrast to R848, polyUs21 induced detectable levels of intracellular interferon-alpha (IFN-alpha) in plasmacytoid dendritic cells (PDCs). In immunization studies, only polyUs21 led to robust priming of type 1 T helper cells and cytotoxic T lymphocytes, and it was more efficient in inducing antitumor immunity than R848. Notably, exogenous IFN-alpha augmented the adjuvant activity of R848, whereas depletion of PDC abrogated the adjuvanticity of polyUs21. This study, therefore, identifies sufficient IFN-alpha production by PDC as an important determinant of vaccine efficacy. (Blood. 2010; 115: 1949-1957)