TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection.
TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection.
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DOI：
10.4049/jimmunol.1002845
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发表时间：
2011-02-15
期刊：
影响因子：
--
通讯作者：
Segal DM
中科院分区：
文献类型：
--
作者：
Jelinek I;Leonard JN;Price GE;Brown KN;Meyer-Manlapat A;Goldsmith PK;Wang Y;Venzon D;Epstein SL;Segal DM
树突状细胞(DC)成熟为有能力的APC是产生获得性免疫的关键，也是佐剂的主要功能。DsRNA是病毒感染的分子标志，通过激活TLR3来驱动DC成熟，但激活DC所需的dsRNA大小和TLR3蛋白在DC亚群中的表达模式尚未确定。在这里，我们发现交叉激发的CD8、α+和CD103+DC亚群比其他DC表达更高水平的TLR3。在静息DC中，TLR3定位于早期的内小体和其他细胞内，但在TLR3配体的刺激下迁移到LAMP1+内小体。使用长度为25~540bp的均一dsRNA寡核苷酸，我们观察到最小长度约90bp就足以诱导CD86、IL12p40、干扰素-β、肿瘤坏死因子-α和IL-6的表达，并使DC成熟为APC，向CD8+T细胞交叉递呈外源抗原。TLR3是dsRNA ONS激活DC所必需的，其激活效力随dsRNA长度的增加而增加，并因DC亚群的不同而异。在体内，dsRNA ONS以大小依赖的方式作为佐剂产生抗原特异性CTL，并在与流感核蛋白作为免疫原时诱导对流感病毒的致死性攻击的保护。这些结果为开发TLR3特异性佐剂提供了基础，这些佐剂能够诱导针对病毒病原体的免疫反应。
Maturation of dendritic cells (DC) to competent APC is essential for the generation of acquired immunity and is a major function of adjuvants. dsRNA, a molecular signature of viral infection, drives DC maturation by activating TLR3, but the size of dsRNA required to activated DC and the expression patterns of TLR3 protein in DC subsets have not been established. Here we show that cross-priming CD8α+ and CD103+ DC subsets express much higher levels of TLR3 than other DC. In resting DC, TLR3 is located in early endosomes and other intracellular compartments but migrates to LAMP1+ endosomes upon stimulation with a TLR3 ligand. Using homogeneous dsRNA oligonucleotides (ONs) ranging in length from 25 to 540 bp, we observed that a minimum length of about 90 bp was sufficient to induce CD86, IL12p40, IFN-β, TNF-α, and IL-6 expression and to mature DC into APC that cross-presented exogenous antigens to CD8+ T cells. TLR3 was essential for activation of DC by dsRNA ONs, and the potency of activation increased with dsRNA length and varied between DC subsets. In vivo, dsRNA ONs, in a size-dependent manner, served as adjuvants for the generation of antigen-specific CTL and for inducing protection against lethal challenge with influenza virus when given with influenza nucleoprotein as an immunogen. These results provide the basis for the development of TLR3-specific adjuvants capable of inducing immune responses tailored for viral pathogens.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1084/jem.192.12.1685
发表时间：
2000-12-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
den Haan JM;Lehar SM;Bevan MJ
通讯作者：
Bevan MJ
影响因子：
30.5
作者：
Bedoui, Sammy;Whitney, Paul G.;Heath, William R.
通讯作者：
Heath, William R.
DOI：
10.1126/science.1183021
发表时间：
2010-01-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iwasaki A;Medzhitov R
通讯作者：
Medzhitov R
DOI：
10.1084/jem.20092140
发表时间：
2010-06-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jongbloed SL;Kassianos AJ;McDonald KJ;Clark GJ;Ju X;Angel CE;Chen CJ;Dunbar PR;Wadley RB;Jeet V;Vulink AJ;Hart DN;Radford KJ
通讯作者：
Radford KJ