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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo
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ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo

机译：ESAT-6 依赖性胞质模式识别驱动体内非同源结核病控制

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摘要

IFN-gamma is a critical mediator of host defense against Mycobacterium tuberculosis (Mtb) infection. Antigen-specific CD4(+) T cells have long been regarded as the main producer of IFN-gamma in tuberculosis (TB), and CD4+ T cell immunity is the main target of current TB vaccine candidates. However, given the recent failures of such a TB vaccine candidate in clinical trials, strategies to harness CD4-independent mechanisms of protection should be included in future vaccine design. Here, we have reported that noncognate IFN-gamma production by Mtb antigen-independent memory CD8(+) T cells and NK cells is protective during Mtb infection and evaluated the mechanistic regulation of IFN-gamma production by these cells in vivo. Transfer of arenavirus- or protein-specific CD8(+) T cells or NK cells reduced the mortality and morbidity rates of mice highly susceptible to TB in an IFN-gamma-dependent manner. Secretion of IFN-gamma by these cell populations required IL-18, sensing of mycobacterial viability, Mtb protein 6-kDa early secretory antigenic target-mediated (ESAT-6-mediated) cytosolic contact, and activation of NLR family pyrin domain-containing protein 3 (NLRP3) inflammasomes in CD11c(+) cell subsets. Neutralization of IL-18 abrogated protection in susceptible recipient mice that had received noncognate cells. Moreover, improved Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine-induced protection was lost in the absence of ESAT-6-dependent cytosolic contact. Our findings provide a comprehensive mechanistic framework for antigen-independent IFN-gamma secretion in response to Mtb with critical implications for future intervention strategies against TB.
机译：IFN-γ 是宿主防御结核分枝杆菌 （Mtb） 感染的关键介质。抗原特异性CD4（+）T细胞长期以来一直被认为是结核病（TB）中IFN-γ的主要生产者，CD4+ T细胞免疫是当前结核病候选疫苗的主要靶点。然而，鉴于这种结核病候选疫苗最近在临床试验中的失败，在未来的疫苗设计中应包括利用CD4非依赖性保护机制的策略。在这里，我们报道了 Mtb 抗原非依赖性记忆 CD8（+） T 细胞和 NK 细胞产生的非同源 IFN-γ 在 Mtb 感染期间具有保护作用，并评估了这些细胞在体内产生 IFN-γ 的机制调节。沙粒病毒或蛋白质特异性CD8（+）T细胞或NK细胞的转移以IFN-γ依赖性方式降低了高度易感结核病小鼠的死亡率和发病率。这些细胞群分泌 IFN-γ 需要 IL-18、分枝杆菌活力的感应、Mtb 蛋白 6-kDa 早期分泌抗原靶标介导的（ESAT-6 介导）胞质接触以及 CD11c（+） 细胞亚群中 NLR 家族含 pyrin 结构域蛋白 3 （NLRP3） 炎症小体的激活。IL-18的中和消除了对接受非同源细胞的易感受体小鼠的保护作用。此外，在没有 ESAT-6 依赖性胞质接触的情况下，改进的牛分枝杆菌卡介苗 （BCG） 疫苗诱导的保护作用丧失。我们的研究结果为抗原非依赖性IFN-γ分泌响应Mtb提供了一个全面的机制框架，对未来的结核病干预策略具有重要意义。

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