Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner.
Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner.
复制标题
DOI：
10.1371/journal.ppat.1002378
复制
发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Das G
中科院分区：
文献类型：
--
作者：
Chatterjee S;Dwivedi VP;Singh Y;Siddiqui I;Sharma P;Van Kaer L;Chattopadhyay D;Das G
尽管卡介苗（Bacillus calmette - gusamrin， BCG）的疗效相对较差，但自1921年问世以来，它一直被用作结核病（TB）疫苗。卡介苗诱导强大的辅助性T 1 （Th1）免疫应答，但对许多个体来说，这还不足以使宿主抵抗结核分枝杆菌（M. tb）感染。本研究提供的证据表明，早期分泌的抗原靶蛋白6 (ESAT-6)，由毒力强的结核分枝杆菌H37Rv株表达，而不是由卡介苗表达，可促进疫苗增强的Th17细胞反应。ESAT-6的这些活性依赖于TLR-2/MyD88信号，并参与树突状细胞产生IL-6和TGF-β。因此，先前感染过H37Rv或含有RD1区域的重组卡介苗（BCG::RD1）的动物与先前感染过卡介苗或RD1缺陷的H37Rv的小鼠相比，在毒力强的H37Rv再次攻击时表现出更好的保护作用（H37RvΔRD1）。然而，TLR-2敲除（TLR-2-/-）的动物既没有表现出Th17反应，也没有对H37Rv免疫表现出更好的保护作用。此外，H37Rv和BCG::RD1感染对树突状细胞（dc）中抗炎microRNA-146a （miR146a）的表达影响不大，而BCG和H37RvΔRD1则能显著诱导其在dc中的表达。与这些发现一致，ESAT-6对未感染的dc中的miR146a表达没有影响，但在bcg感染或lps处理的dc中显著抑制其上调。总之，我们的研究结果表明，除了卡介苗诱导的Th1免疫应答外，RD1/ esat -6诱导的Th17免疫应答对于疫苗的最佳效果至关重要。结核病是一个全球性的健康问题，全球三分之一的人口感染了结核杆菌。大量研究表明，Th1细胞反应对于结核病的保护性免疫是必不可少的。然而，虽然疫苗株卡介苗诱导了足够的Th1细胞反应，但这种反应似乎不足以对许多个体产生免疫保护。在这里，我们首次提供了证据，证明Th17细胞在肺中的反应在增强对结核病的保护中起着关键作用。令人惊讶的是，毒力强的结核分枝杆菌H37Rv在肺部诱导Th17细胞反应。因此，先前感染过H37Rv的经抗生素治疗的动物，与同样处理过bcg的感染小鼠相比，对强毒性结核分枝杆菌感染产生了更好的保护性免疫反应。我们还提供证据表明，在BCG中不存在而在H37Rv中存在的ESAT-6蛋白以TLR-2和myd88依赖的方式诱导树突状细胞中的IL-6和TGF-β，从而产生有利于Th17细胞在肺中分化的环境。我们的研究结果表明，除了Th1细胞外，Th17细胞在提供最佳的结核病保护中起着关键作用。
Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2-/-) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy. Tuberculosis is a global health problem, with one-third of the global population infected with tubercle bacteria. Numerous studies have shown that Th1 cell responses are indispensable for protective immunity against TB. However, while the vaccine strain BCG induces sufficient Th1 cell response, this response does not appear to be sufficient for immune protection in many individuals. Here, we provide evidence for the first time that Th17 cell responses in the lung play a critical role for enhanced protection against TB. Surprisingly, the virulent M. tb strain H37Rv induced Th17 cell responses in the lung. Consequently, antibiotic-treated animals that were previously infected with H37Rv, as compared with similarly treated BCG-infected mice, generated improved protective immune responses against infection with virulent M. tb. We also provide evidence that the ESAT-6 protein, which is absent in BCG but present in H37Rv, induces IL-6 and TGF-β in dendritic cells in a TLR-2 and MyD88-dependent manner, which generates an environment that is conducive for the differentiation of Th17 cells in the lung. Our findings indicate that, in addition to Th1 cells, Th17 cells play a critical role in conferring optimal protection against TB.
登录
查看更多内容
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
15.9
作者：
Ito, Toshihiro;Schaller, Matthew;Kunkel, Steven L.
通讯作者：
Kunkel, Steven L.
影响因子：
3.2
作者：
Ganguly, Niladri;Siddiqui, Imran;Sharma, Pawan
通讯作者：
Sharma, Pawan
影响因子：
4.9
作者：
Kelly, BP;Furney, SK;Orme, IM
通讯作者：
Orme, IM
影响因子：
32.4
作者：
Devadas, Satish;Das, Jyoti;Shi, Yufang
通讯作者：
Shi, Yufang