ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo
ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo
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DOI：
10.1172/jci84978
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发表时间：
2016-06-01
影响因子：
15.9
通讯作者：
Kaufmann, Stefan H. E.
中科院分区：
文献类型：
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作者：
Kupz, Andreas;Zedler, Ulrike;Kaufmann, Stefan H. E.
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CD 4（+）T细胞一直被认为是结核病（TB）中IFN-γ的主要产生者，并且CD 4 + T细胞免疫是当前TB候选疫苗的主要靶点。然而，鉴于最近这种结核病候选疫苗在临床试验中的失败，在未来的疫苗设计中应包括利用CD 4非依赖性保护机制的策略。在这里，我们已经报道了Mtb抗原非依赖性记忆CD 8（+）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，并评估了这些细胞体内IFN-γ产生的机制调节。沙粒病毒或蛋白特异性CD 8（+）T细胞或NK细胞的转移以IFN-γ依赖的方式降低了对TB高度易感的小鼠的死亡率和发病率。这些细胞群分泌IFN-γ需要IL-18、检测分枝杆菌活力、Mtb蛋白6-kDa早期分泌抗原靶点介导（ESAT-6介导）的胞质接触以及活化CD 11 c（+）细胞亚群中的NLR家族含pyrin结构域蛋白3（NLRP 3）炎性小体。IL-18的中和废除了接受非同源细胞的易感受体小鼠中的保护。此外，在缺乏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。我们的研究结果提供了一个全面的机制框架，抗原非依赖性IFN-γ分泌响应结核分枝杆菌与未来的结核病干预策略的关键影响。
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.