Impaired Function of CTLA-4 in the Lungs of Patients with Chronic Beryllium Disease Contributes to Persistent Inflammation
Impaired Function of CTLA-4 in the Lungs of Patients with Chronic Beryllium Disease Contributes to Persistent Inflammation
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DOI：
10.4049/jimmunol.1300282
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发表时间：
2013-08-15
影响因子：
4.4
通讯作者：
Fontenot, Andrew P.
中科院分区：
文献类型：
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作者：
Chain, Jennifer L.;Martin, Allison K.;Fontenot, Andrew P.
慢性铍病 (CBD) 是一种职业性肺部疾病，其特征是肉芽肿性炎症和铍反应性 CD4(+) T 细胞在肺部积聚。这些分化的效应记忆 T 细胞在体外激活后会分泌 IL-2、IFN-γ 和 TNF-α。肺中的铍反应性 CD4+ T 细胞不依赖于 CD28，并且共抑制受体（程序性死亡 1）的表达增加，导致 Ag 特异性 T 细胞增殖不良，但仍保留表达 Th1 型细胞因子的能力。为了进一步研究共抑制受体在铍诱导的免疫反应中的作用，我们检测了 CBD 受试者的血液和支气管肺泡灌洗细胞中 CTLA-4 的表达。与血液相比，研究对象肺部 CD4(+) T 细胞的 CTLA-4 表达升高。此外，CTLA-4在铍反应性CD4+T细胞亚群中表达最高，该亚群保留了增殖和表达IL-2的能力。功能分析表明，血细胞中CTLA-4信号的诱导抑制了铍诱导的T细胞增殖，但对肺中铍响应性CD4(+) T细胞的增殖能力没有影响。总的来说，我们的研究结果表明肺部 CTLA-4 通路功能失调，及其对 CBD 特征的持续炎症反应的潜在贡献。
Chronic beryllium disease (CBD) is an occupational lung disorder characterized by granulomatous inflammation and the accumulation of beryllium-responsive CD4(+) T cells in the lung. These differentiated effector memory T cells secrete IL-2, IFN-gamma, and TNF-alpha upon in vitro activation. Beryllium-responsive CD4(+) T cells in the lung are CD28 independent and have increased expression of the coinhibitory receptor, programmed death 1, resulting in Ag-specific T cells that proliferate poorly yet retain the ability to express Th1-type cytokines. To further investigate the role of coinhibitory receptors in the beryllium-induced immune response, we examined the expression of CTLA-4 in blood and bronchoalveolar lavage cells from subjects with CBD. CTLA-4 expression was elevated on CD4(+) T cells from the lungs of study subjects compared with blood. Furthermore, CTLA-4 expression was greatest in the beryllium-responsive subset of CD4(+) T cells that retained the ability to proliferate and express IL-2. Functional assays show that the induction of CTLA-4 signaling in blood cells inhibited beryllium-induced T cell proliferation while having no effect on the proliferative capacity of beryllium-responsive CD4(+) T cells in the lung. Collectively, our findings suggest a dysfunctional CTLA-4 pathway in the lung and its potential contribution to the persistent inflammatory response that characterizes CBD.