Tan Dino B A, Teo Teck-Hui, Setiawan Abdul M, Ong Nathanael E, Zimmermann Maja, Price Patricia, Kirkham Lea-Ann S, Moodley Yuben P
Centre for Respiratory Health, School of Medicine & Pharmacology, University of Western Australia, Perth, WA, Australia.
Stem Cell Unit, Institute of Respiratory Health, Perth, WA, Australia.
Immunology. 2017 Jun;151(2):219-226. doi: 10.1111/imm.12725. Epub 2017 Mar 20.
Impaired T helper type 1 (Th1) function is implicated in the susceptibility of patients with chronic obstructive pulmonary disease (COPD) to respiratory infections, which are common causes of acute exacerbations of COPD (AECOPD). To understand the underlying mechanisms, we assessed regulatory T (Treg) cells and the expression of an inhibitory T-cell receptor, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Cryopreserved peripheral blood mononuclear cells (PBMC) from patients with AECOPD (n = 17), patients with stable COPD (sCOPD; n = 24) and age-matched healthy non-smoking controls (n = 26) were cultured for 24 hr with brefeldin-A or monensin to detect intracellular or surface CTLA-4 (respectively) by flow cytometry. T cells in PBMC from AECOPD (n = 9), sCOPD (n = 14) and controls (n = 12) were stimulated with anti-CD3 with and without anti-CTLA-4 blocking antibodies and cytokines were quantified by ELISA. Frequencies of circulating T cells expressing intracellular CTLA-4 were higher in sCOPD (P = 0·01), whereas patients with AECOPD had more T cells expressing surface CTLA-4 than healthy controls (P = 0·03). Increased frequencies of surface CTLA-4 CD4 T cells and CTLA-4 Treg cells paralleled increases in plasma soluble tumour necrosis factor receptor-1 levels (r = 0·32, P = 0·01 and r = 0·29, P = 0·02, respectively) in all subjects. Interferon-γ responses to anti-CD3 stimulation were inversely proportional to frequencies of CD4 T cells expressing intracellular CTLA-4 (r = -0·43, P = 0·01). Moreover, CTLA-4 blockade increased the induction of interferon-γ, tumour necrosis factor-α and interleukin-6 in PBMC stimulated with anti-CD3. Overall, chronic inflammation may expand sub-populations of T cells expressing CTLA-4 in COPD patients and therefore impair T-cell function. CTLA-4 blockade may restore Th1 function in patients with COPD and so aid the clearance of bacterial pathogens responsible for AECOPD.
1型辅助性T细胞（Th1）功能受损与慢性阻塞性肺疾病（COPD）患者易发生呼吸道感染有关，而呼吸道感染是COPD急性加重（AECOPD）的常见原因。为了解其潜在机制，我们评估了调节性T（Treg）细胞以及抑制性T细胞受体细胞毒性T淋巴细胞相关抗原4（CTLA-4）的表达。将来自AECOPD患者（n = 17）、稳定期COPD（sCOPD；n = 24）患者和年龄匹配的健康非吸烟对照者（n = 26）的冻存外周血单核细胞（PBMC）与布雷菲德菌素A或莫能菌素培养24小时，分别通过流式细胞术检测细胞内或表面的CTLA-4。用抗CD3刺激来自AECOPD患者（n = 9）、sCOPD患者（n = 14）和对照者（n = 12）的PBMC中的T细胞，并使用抗CTLA-4阻断抗体，通过酶联免疫吸附测定法（ELISA）对细胞因子进行定量。sCOPD患者中表达细胞内CTLA-4的循环T细胞频率更高（P = 0.01），而AECOPD患者中表达表面CTLA-4的T细胞比健康对照者更多（P = 0.03）。在所有受试者中，表面CTLA-4 CD4 T细胞和CTLA-4 Treg细胞频率的增加与血浆可溶性肿瘤坏死因子受体-1水平的增加平行（r分别为0.32，P = 0.01和r = 0.29，P = 0.02）。对抗CD3刺激的干扰素-γ反应与表达细胞内CTLA-4的CD4 T细胞频率成反比（r = -0.43，P = 0.01）。此外，CTLA-4阻断增加了抗CD3刺激的PBMC中干扰素-γ、肿瘤坏死因子-α和白细胞介素-6的诱导。总体而言，慢性炎症可能会扩大COPD患者中表达CTLA-4的T细胞亚群，从而损害T细胞功能。CTLA-4阻断可能会恢复COPD患者的Th1功能，从而有助于清除导致AECOPD的细菌病原体。
