Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis
Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis
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DOI：
10.1164/rccm.201509-1746oc
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发表时间：
2016-08-01
影响因子：
24.7
通讯作者：
Stenger, Steffen
中科院分区：
文献类型：
--
作者：
Busch, Martin;Herzmann, Christian;Stenger, Steffen
理论基础：要发展针对宿主的、预防和治疗结核病的干预措施，需要更好地了解决定结核分枝杆菌感染结局的免疫机制。目的：确定在结核病中具有保护作用的T细胞依赖机制。方法：采用多色流式细胞术、细胞分类和生长抑制试验比较来自支气管肺泡灌洗液或外周血的T淋巴细胞的频率、表型和功能。测量和主要结果：在两个独立的研究地点，来自潜在结核感染的供者的支气管肺泡灌洗液细胞比那些患有疾病的患者的T淋巴细胞更有效地限制了毒力结核分枝杆菌的生长。非传统的糖脂反应性T细胞有助于减少分枝杆菌的生长，因为CD1b的抗体抑制了55%的这种作用。脂肪阿拉伯甘露聚糖是最有效的分枝杆菌脂抗原(可激活1.3%的T淋巴细胞)，并激活CD1b限制的T细胞，限制细菌生长。产生干扰素-γ的脂肪阿拉伯甘露聚糖反应性T细胞亚群共表达细胞毒分子穿孔素、颗粒溶素和颗粒酶B，我们称之为多细胞毒性T细胞。利用潜伏感染结核分枝杆菌或感染后发展为活动性疾病的患者的两个明确的队列，我们发现多细胞毒性T细胞的频率与控制感染的能力之间存在相关性(潜伏的结核病感染，62%；结核病后患者，26%)。结论：我们的数据定义了基于抗原识别和功能的非传统CD8(+)T细胞亚群(多细胞毒性T细胞)。这一结果将糖脂反应的多细胞毒性T细胞有助于预防结核病的临床和机制证据联系在一起。
Rationale: The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis.Objectives: To identify T-cell-dependent mechanisms that are protective in tuberculosis.Methods: Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood.Measurements and Main Results: At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-gamma-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%).Conclusions: Our data define an unconventional CD8(+) T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.