Programmed death-1+ T cells inhibit effector T cells at the pathological site of miliary tuberculosis
Programmed death-1+ T cells inhibit effector T cells at the pathological site of miliary tuberculosis
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DOI：
10.1111/cei.12871
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发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Mitra, D. K.
中科院分区：
文献类型：
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作者：
Singh, A.;Mohan, A.;Mitra, D. K.
最佳的T细胞活化对于成功解决微生物感染至关重要。程序性死亡-1（PD-1）是由活化的T细胞表达的关键免疫检查点受体。PD-1介导的异常/过度抑制可能会损害宿主对结核分枝杆菌感染的免疫力，导致播散性疾病，如粟粒性结核病（MTB）。报道了PD-1介导的对肺结核和TB胸膜炎中T细胞的抑制。然而，它们在MTB中的作用，特别是在病理部位，仍有待解决。本研究的目的是研究PD-1-PD-配体1（PD-L1）在结核性胸膜炎和结核分枝杆菌（MTB）患者病理部位T细胞应答中的作用，结核性胸膜炎和结核分枝杆菌分别作为结核病的临床模型。我们检测了结核病患者中PD-1及其配体（PD-L1-PD-L2）在宿主免疫细胞上的表达和功能。MTB中支气管肺泡灌洗衍生的CD 3 T细胞表达PD-1（54.2 +/-27.4%，P >= 0.0009），PD-1配体阳性T细胞显著升高（PD-L1：19.8 ± 11.8%; P >= 0.019; PD-L2：12.6 ± 6.2%; P >= 0.023），CD 19（+）B细胞（PD-L1：14.4 +/- 10.4%; P >= 0.042，PD-L2：2.6 +/- 1.43%;不显著）和CD 14（+）单核细胞（PD-L1：40.2 +/- 20.1%; P >= 0.047，PD-L2：22.4 +/- 15.6%; P >= 0.032）与MTB和健康对照的外周血（PB）相比。PD-1的表达与产生效应细胞因子干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α、白细胞介素（IL）22的细胞数量减少和细胞凋亡增加相关。局部聚集的T细胞主要是PD-1（+）-PD-L1（+），阻断这一途径可恢复保护性T细胞反应。我们的结论是M.结核病利用PD-1途径通过改变MTB病理部位的1型辅助T细胞（Th 1）和Th 2平衡来逃避宿主免疫应答，从而有利于疾病传播。
Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death-1 (PD-1) is a key immune check-point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD-1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD-1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD-1-PD-ligand 1 (PD-L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD-1 and its ligands (PD-L1-PD-L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage-derived CD3 T cells in MTB expressed PD-1 (54.2 +/- 27.4%, P >= 0.0009) with significantly higher PD-1 ligand-positive T cells (PD-L1: 19.8 +/- 11.8%; P >= 0.019, PD-L2: 12.6 +/- 6.2%; P >= 0.023), CD19(+) B cells (PD-L1: 14.4 +/- 10.4%; P >= 0.042, PD-L2: 2.6 +/- 1.43%; not significant) and CD14(+) monocytes (PD-L1: 40.2 +/- 20.1%; P >= 0.047, PD-L2: 22.4 +/- 15.6%; P >= 0.032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD-1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL) 22 and elevated apoptosis. Locally accumulated T cells were predominantly PD-1(+)-PD-L1(+), and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD-1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby favouring disease dissemination.