Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain.
Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain.
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DOI：
10.18632/oncotarget.8771
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Shin SJ
中科院分区：
文献类型：
--
作者：
Kim WS;Kim JS;Cha SB;Kim H;Kwon KW;Kim SJ;Han SJ;Choi SY;Cho SN;Park JH;Shin SJ
鉴定诱导Ag特异性Th 1免疫的疫苗靶抗原（Ags）是开发结核病疫苗的第一步。在这里，我们评估了结核分枝杆菌（Mtb）蛋白Rv 3628，可溶性无机焦磷酸酶，作为疫苗的目标，其特征在于与树突状细胞（DC）的相互作用的分子细节。Rv 3628激活DC，增加其细胞表面分子的表达并增加其TNF-α、IL-1β、IL-6和IL-12 p70的产生。Rv 3628通过与TLR 2结合并激活下游MyD 88、MAPK和NF-κ B依赖性信号通路介导这些作用。Rv 3628刺激的DC诱导OVA特异性CD 4+和CD 8 + T细胞的扩增，其分泌IFN-γ和IL-2。Rv 3628特异性效应/记忆T细胞扩增到与从Mtb感染小鼠收集的肺和脾细胞样品中用ESAT-6 Ag刺激的那些相似的程度。最后，用含有单磷酰脂质-A的二甲基双十八烷基铵脂质体作为佐剂的Rv 3628亚单位疫苗在用超毒力Mtb K菌株攻击后引起细菌计数和肺部炎症的显著减少。重要的是，保护效力与Rv 3628特异性CD 4 + T细胞的产生相关，所述CD 4 + T细胞共产生IFN-γ、TNF-α和IL-2，并表现出升高的IFN-γ回忆应答。因此，Rv 3628使DC向Th 1表型极化并促进针对Mtb感染的保护性免疫。
Identification of vaccine target antigens (Ags) that induce Ag-specific Th1 immunity is the first step toward the development of a tuberculosis vaccine. Here, we evaluated the Mycobacterium tuberculosis (Mtb) protein Rv3628, a soluble inorganic pyrophosphatase, as a vaccine target and characterized the molecular details of its interaction with dendritic cells (DCs). Rv3628 activated DCs, increasing their expression of cell surface molecules and augmenting their production of TNF-α, IL-1β, IL-6, and IL-12p70. Rv3628 mediated these effects by binding to TLR2 and activating downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. Rv3628-stimulated DCs induced the expansion of OVA-specific CD4+ and CD8+ T cells, which secreted IFN-γ and IL-2. Rv3628-specific effector/memory T cells expanded to a similar extent as those stimulated with ESAT-6 Ag in samples of lung and spleen cells collected from Mtb-infected mice. Finally, an Rv3628 subunit vaccine adjuvanted with dimethyldioctadecylammonium liposomes containing monophosphoryl lipid-A caused significant reductions in bacterial counts and lung inflammation after challenge with the hyper-virulent Mtb K strain. Importantly, protective efficacy was correlated with the generation of Rv3628-specific CD4+ T cells co-producing IFN-γ, TNF-α and IL-2 and exhibiting an elevated IFN-γ recall response. Thus, Rv3628 polarizes DCs toward a Th1 phenotype and promotes protective immunity against Mtb infection.
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影响因子：
82.9
作者：
Harari A;Rozot V;Bellutti Enders F;Perreau M;Stalder JM;Nicod LP;Cavassini M;Calandra T;Blanchet CL;Jaton K;Faouzi M;Day CL;Hanekom WA;Bart PA;Pantaleo G
通讯作者：
Pantaleo G
结核分枝杆菌对抗原呈递的调节：Toll 样受体的作用。
DOI：
10.1038/nrmicro2321
发表时间：
2010-04
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.7
作者：
Chatterjee S;Dwivedi VP;Singh Y;Siddiqui I;Sharma P;Van Kaer L;Chattopadhyay D;Das G
通讯作者：
Das G
DOI：
10.4049/jimmunol.1101122
发表时间：
2011-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Day CL;Abrahams DA;Lerumo L;Janse van Rensburg E;Stone L;O'rie T;Pienaar B;de Kock M;Kaplan G;Mahomed H;Dheda K;Hanekom WA
通讯作者：
Hanekom WA
影响因子：
7
作者：
Gu, S;Chen, J;Chen, X
通讯作者：
Chen, X