T-Regulatory Cells and Programmed Death 1+ T Cells Contribute to Effector T-Cell Dysfunction in Patients with Chronic Obstructive Pulmonary Disease
T-Regulatory Cells and Programmed Death 1+ T Cells Contribute to Effector T-Cell Dysfunction in Patients with Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201312-2293oc
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发表时间：
2014-07-01
影响因子：
24.7
通讯作者：
Thanavala, Yasmin
中科院分区：
文献类型：
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作者：
Kalathil, Suresh Gopi;Lugade, Amit Anand;Thanavala, Yasmin
基本原理：我们实验室先前的研究表明，慢性阻塞性肺疾病（COPD）患者的外周血单核细胞（PBMC）对脂蛋白P6的反应受损，这些患者容易因不可分型的流感嗜血杆菌而加重。我们推测，一个潜在的免疫抑制网络可能是负责在这些患者中观察到的抗菌免疫缺陷。我们评估了调节性T细胞（TCFs）、髓源性抑制细胞（MDSC）和耗竭的效应性T细胞。（程序性死亡1 [PD-1]（+）），因为已知这些细胞在抑制免疫应答中起关键作用。目的：我们对T细胞，T效应细胞，方法：采用流式细胞术检测COPD患者和健康对照者外周血单个核细胞（PBMC）中Treg、效应T细胞和MDSC的表达，并分析其水平和功能与疾病严重程度的相关性。通过体外抑制测定来测量Treg免疫抑制能力。在阻断CTLA-4和PD-1后测量产生干扰素γ的T细胞的频率和T细胞增殖。测量和主要结果：COPD患者与健康受试者相比，TCF 4、MDSC和PD-1（+）耗竭效应T细胞水平显著增加。来自COPD患者的TCL 4抑制P6特异性T细胞增殖的程度大于来自健康受试者的TCL 4。Treg产生的细胞因子、IL-10和转化生长因子-β的血浆水平升高。CTLA-4的阻断导致COPD患者T细胞IFN-γ产生显着增加。结论：功能抑制性Treg、MDSC和耗尽的PD-1（+）T细胞导致COPD患者效应T细胞功能障碍。
Rationale: Previous studies from our laboratory have shown that peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) prone to exacerbations with nontypeable Haemophilus influenzae have impaired responses to lipoprotein P6. We hypothesized that an underlying immunosuppressive network could be responsible for the defective antibacterial immunity observed in these patients. We evaluated T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and exhausted T effector cells (programmed death 1 [PD-1](+)) in patients with COPD, because these cells are known to play a pivotal role in suppressing immune responses.Objectives: We performed an in-depth characterization of Tregs, T effector cells, and MDSC in COPD and correlated their levels and function with disease severity.Methods: Treg, effector T cell, and MDSC frequency from patients with COPD and healthy subjects' PBMCs were analyzed by flow cytometry. Treg immunosuppressive capacity was measured by in vitro suppression assay. The frequency of interferon-gamma producing T cells and T-cell proliferation were measured after blocking CTLA-4 and PD-1. Plasma proinflammatory and immunosuppressive cytokine levels were measured.Measurements and Main Results: Significantly increased levels of Tregs, MDSC, and PD-1(+) exhausted effector T cells were present in patients with COPD compared with healthy subjects. Tregs from patients with COPD suppressed P6-specific T-cell proliferation to a greater extent than Tregs from healthy subjects. Plasma levels of Treg-generated cytokines, IL-10, and transforming growth factor-beta were elevated. Blockade of CTLA-4 resulted in significant augmentation of T-cell IFN-gamma production in patients with COPD.Conclusions: Functionally suppressive Tregs, MDSCs, and exhausted PD-1(+) T cells contribute to effector T-cell dysfunction in COPD.