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Early Secreted Antigen ESAT-6 of Mycobacterium tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like Receptor-2-dependent Manner

机译:结核分枝杆菌的早期分泌抗原ESAT-6以类似Toll受体2的方式促进保护性T辅助17细胞反应。

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摘要

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.
机译:尽管其功效相对较差,但自1921年发展以来,卡介苗芽孢杆菌(BCG)一直被用作结核(TB)疫苗。BCG诱导强大的T辅助1(Th1)免疫反应,但是对于许多人来说,这还不够用于宿主抵抗结核分枝杆菌(M. tb)感染。在这里,我们提供了证据,即由强毒的M. tb菌株H37Rv而不是BCG表达的早期分泌的抗原靶蛋白6(ESAT-6)促进了增强Th17细胞应答的疫苗。 ESAT-6的这些活性取决于TLR-2 / MyD88信号传导,并涉及树突状细胞产生IL-6和TGF-β。因此,与先前感染了BCG或RD1缺陷的H37Rv(H37RvΔRD1)的小鼠相比,先前被H37Rv或含有RD1区(BCG :: RD1)的重组BCG感染的动物在再次受到强毒H37Rv攻击时表现出更好的保护作用。但是,TLR-2基因敲除(TLR-2-/-)动物既没有显示Th17反应,也没有显示出对H37Rv免疫反应的更好保护。此外,H37Rv和BCG :: RD1感染对树突状细胞(DC)中抗炎microRNA-146a(miR146a)的表达影响很小,而BCG和H37RvΔRD1则深刻诱导了其在DC中的表达。与这些发现一致,ESAT-6对未感染的DC中miR146a表达没有影响,但是在BCG感染或LPS处理的DC中显着抑制了其上调。总体而言,我们的研究结果表明,除了BCG诱导的Th1免疫外,RD1 / ESAT-6诱导的Th17免疫应答对于最佳疫苗效力也至关重要。

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