Effect of memory CD4+ T cells' signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma
Effect of memory CD4+ T cells' signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma
复制标题
记忆 CD4 T 细胞的信号转导器和转录激活剂 (STAT) 功能转变对哮喘细胞因子释放特性的影响
DOI：
10.1007/s10565-016-9357-6
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发表时间：
2017-02-01
影响因子：
6.1
通讯作者：
Wang, Xiangdong
中科院分区：
文献类型：
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作者：
Chen, Zhihong;Pan, Jue;Wang, Xiangdong
最近的数据表明，长寿命的记忆T细胞存在于人肺中，并且可以在特定的过敏性和自身免疫性疾病的发病机制中发挥重要作用。然而，大多数证据已经从小鼠研究中获得，并且记忆T细胞在人类过敏性疾病（例如哮喘）中的潜在作用在很大程度上仍然未知。从外周血中分离外周血单个核细胞（PBMC），并进行细胞表面染色（CD 4、CD 45 RO、CRTH 2、CD 62 L和CCR 7）以检测血液中的记忆性CD 4（+）T细胞。分别用白细胞介素-27（IL-27）或IL-4刺激记忆性CD 4（+）T细胞15 min后，流式细胞术检测STAT 1/STAT 6磷酸化水平。在中和、T（H）2、T（H）2 +脂多糖（LPS）和T（H）2 +屋尘螨（HDM）条件下培养6天后，通过细胞内蛋白（IL-5、IL-17和干扰素（IFN）-γ）染色检测IFN-γ释放曲线。哮喘患者外周血中记忆性CD 4（+）T细胞数（CD 4（+）Tm）显著高于健康对照组（48 ± 5.7%vs.32 ± 4.1%，p < 0.05）。与COPD和健康对照组相比，哮喘患者肺组织中STAT 1-py磷酸化水平降低，STAT 6-py磷酸化水平轻度升高。这种STAT 1-py/STAT 6-py的不平衡归因于血液中的T（H）2记忆细胞，而不是非T（H）2记忆细胞。与COPD患者和健康受试者相比，哮喘患者的尼古丁释放曲线是独特的，特别是IL-5（高），IL-17（高）和IFN-γ（低）。CD 4（+）Tm细胞产生IL-17的水平与疾病严重程度相关，与哮喘患者的用药量呈正相关，具有抗原特异性记忆的长寿命CD 4（+）T细胞可能是分析哮喘内源性T细胞亚群的理想候选细胞。记忆性CD 4（+）T细胞表现出STAT磷酸化和特异性精氨酸释放谱的变化，有可能促进对疾病异质性和严重程度的理解，从而为患者提供更个性化的治疗。
Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown.Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood, and cell surface staining (CD4, CD45RO, CRTH2, CD62L, and CCR7) was performed for the detection of memory CD4(+) T cells in blood. After stimulation with interleukin-27 (IL-27) or IL-4 for 15 min, the STAT1/STAT6 phosphorylation of memory CD4(+) T cells was measured separately by flow cytometric techniques. The cytokine-releasing profiles after 6 days of culture under neutralization, T(H)2, T(H)2 + lipopolysaccharide (LPS), and T(H)2 + house dust mite (HDM) conditions were detected by intracellular protein (IL-5, IL-17, and interferon (IFN)-gamma) staining. Correlation analyses between the profile of memory CD4(+) T cells and clinical characteristics of asthma were performed.The number of circulating memory CD4(+) T (CD4(+) Tm) cells in asthmatics was increased compared with that in the healthy subjects (48 +/- 5.7 % vs. 32 +/- 4.1 %, p < 0.05). Compared with COPD and healthy subjects, the phosphorylation of signal transducer and activator of transcription 1 (STAT1-py) was impaired in asthmatics, whereas the phosphorylation of signal transducer and activator of transcription 6 (STAT6-py) was slightly enhanced. This imbalance of STAT1-py/STAT6-py was attributed to T(H)2 memory cells but not non-T(H)2 memory cells in blood. The cytokine-releasing profiles of asthmatics was unique, specifically IL-5(high), IL-17(high), and IFN-r(low), compared with those of COPD patients and healthy subjects. The IL-17 production levels in CD4(+) Tm cells are associated with disease severity and positively correlated with medication consumption in asthma.The long-lived, antigen-specific memory CD4(+) T cells, rather than PBMCs or peripheral lymphocytes, might be the ideal T cell subset candidates for analyzing the endotype of asthma. Memory CD4(+) T cells exhibiting a shift in STAT phosphorylation and specific cytokine-releasing profiles have the potential to facilitate the understanding of disease heterogeneity and severity, allowing the more personalized treatment of patients.