Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection
Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection
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DOI：
10.1152/ajplung.00135.2015
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发表时间：
2015-08-01
影响因子：
4.9
通讯作者：
Lawrence, B. Paige
中科院分区：
文献类型：
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作者：
Boule, Lisbeth A.;Winans, Bethany;Lawrence, B. Paige
呼吸道感染是对全球健康和经济的威胁，但感染严重程度惊人变化的基础尚未完全了解。发育期间的环境暴露与生命后期呼吸道感染的严重程度和发病率增加有关。这些暴露中的许多包括芳烃受体（AHR）的配体，芳烃受体是由免疫和非免疫细胞表达的转录因子。在成年动物中，AHR激活会改变CD 4（+）T细胞并改变免疫病理学。发育中的AHR激活影响淋巴组织中的CD 4（+）T细胞反应，但在感染的肺中是否也存在偏斜反应尚不清楚。为了确定肺CD 4（+）T细胞反应是否被发育中的AHR激活所改变，小鼠在发育期间暴露于原型AHR配体2，3，7，8-四氯二苯并-p-二恶英，并在成年时感染流感病毒。与对照组相比，暴露后代的肺具有更大的支气管肺炎炎症，并且活化的病毒特异性CD 4（+）T细胞有助于浸润白细胞。这些效应是CD 4（+）T细胞亚群特异性的，在T辅助1型和调节性T细胞的增加，但在T辅助17型细胞在感染的肺中的频率没有变化。这与先前报道的淋巴结中抑制的常规CD 4（+）T细胞应答形成直接对比。利用过继转移和操纵病原体特性，我们确定发育暴露影响CD 4（+）T细胞的内在和外在因素，并可能涉及发育诱导的受感染肺上皮细胞信号变化。因此，发育暴露导致肺CD 4（+）T细胞亚群的环境依赖性变化，这可能有助于对呼吸道感染的不同反应。
Respiratory infections are a threat to health and economies worldwide, yet the basis for striking variation in the severity of infection is not completely understood. Environmental exposures during development are associated with increased severity and incidence of respiratory infection later in life. Many of these exposures include ligands of the aryl hydrocarbon receptor (AHR), a transcription factor expressed by immune and nonimmune cells. In adult animals, AHR activation alters CD4(+) T cells and changes immunopathology. Developmental AHR activation impacts CD4(+) T-cell responses in lymphoid tissues, but whether skewed responses are also present in the infected lung is unknown. To determine whether pulmonary CD4(+) T-cell responses are modified by developmental AHR activation, mice were exposed to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin during development and infected with influenza virus as adults. Lungs of exposed offspring had greater bronchopulmonary inflammation compared with controls, and activated, virus-specific CD4(+) T cells contributed to the infiltrating leukocytes. These effects were CD4(+) T cell subset specific, with increases in T helper type 1 and regulatory T cells, but no change in the frequency of T helper type 17 cells in the infected lung. This is in direct contrast to prior reports of suppressed conventional CD4(+) T-cell responses in the lymph node. Using adoptive transfers and manipulating the pathogen properties, we determined that developmental exposure influenced factors intrinsic and extrinsic to CD4(+) T cells and may involve developmentally induced changes in signals from infected lung epithelial cells. Thus developmental exposures lead to context-dependent changes in pulmonary CD4(+) T-cell subsets, which may contribute to differential responses to respiratory infection.