Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.
Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.
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DOI：
10.1371/journal.ppat.1004975
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Joyce S
中科院分区：
文献类型：
--
作者：
Hill TM;Gilchuk P;Cicek BB;Osina MA;Boyd KL;Durrant DM;Metzger DW;Khanna KM;Joyce S
呼吸道粘膜是病原体侵入的主要部位，因此是需要持续免疫监视的部位。I型半恒定自然杀伤T（NKT）细胞在肺脉管系统内富集。尽管定位最佳，但NKT细胞在呼吸道传染病中的作用仍然知之甚少。因此，我们评估了它们在肺土拉菌病小鼠模型中的功能，因为土拉菌病是一种脓毒症样促炎性疾病，已知NKT细胞控制脓毒症的细胞和体液反应。在这里，我们首次表明，呼吸道感染与土拉热弗朗西丝菌活疫苗株导致NKT细胞在肺结核内的快速积累。活化的NKT细胞产生干扰素-γ并促进局部和全身促炎反应。与这些结果一致，NKT细胞缺陷型小鼠显示炎性细胞因子和趋化因子反应降低，但它们比野生型小鼠更好地在感染中存活。令人惊讶的是，NKT细胞缺陷小鼠在肺部的淋巴细胞浸润增加，在感染高峰期组织成三级淋巴结构，类似于诱导支气管相关淋巴组织（iBALT）。因此，F.土拉菌感染阻碍了iBALT的形成，并促进了全身性促炎反应，这加剧了小鼠中严重的肺土拉菌样疾病。NKT细胞是先天性的淋巴细胞样细胞，在广泛的疾病中发挥作用。它们经常因其在活化时快速产生各种细胞因子的能力而被引用，它们长期以来因其“启动”免疫系统并塑造先天和适应性反应的质量的能力而受到赞赏。对它们功能的这种理解是从体外实验或通过体内施用高效的化学合成的脂质配体推导出来的，其可能不一定反映在自然感染中观察到的生理学相关反应。利用小鼠肺土拉菌病模型，我们报告了经鼻感染F。土拉热迅速激活NKT细胞并促进全身性炎症、增加的组织损伤和失调的免疫应答，导致感染小鼠的发病率和死亡率增加。我们的数据强调了NKT细胞活化的有害作用，并确定了肺土拉菌病治疗的潜在新靶点。
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia—because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice. NKT cells are innate-like lymphocytes with a demonstrated role in a wide range of diseases. Often cited for their ability to rapidly produce a variety of cytokines upon activation, they have long been appreciated for their ability to “jump-start” the immune system and to shape the quality of both the innate and adaptive response. This understanding of their function has been deduced from in vitro experiments or through the in vivo administration of highly potent, chemically synthesized lipid ligands, which may not necessarily reflect a physiologically relevant response as observed in a natural infection. Using a mouse model of pulmonary tularemia, we report that intranasal infection with the live vaccine strain of F. tularensis rapidly activates NKT cells and promotes systemic inflammation, increased tissue damage, and a dysregulated immune response resulting in increased morbidity and mortality in infected mice. Our data highlight the detrimental effects of NKT cell activation and identify a potential new target for therapies against pulmonary tularemia.
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