CD4 T CELLS: LESSONS LEARNED FROM ASTHMA

CD4 T 细胞：从哮喘中吸取的教训

• 批准号: 7381079
• 负责人: Laurie A Whittaker
• 金额: $ 33.1万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381079
• 关键词: CD4; CELLS; LESSONS; LEARNED; ASTHMA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystic Fibrosis (CF) is a common, lethal genetic disease that arises from defects in CF transmembrane conductance regulator (CFTR). The majority of patients with CF die of progressive respiratory failure and despite over a half a century of research on CF lung disease, our knowledge of its pathogenesis remains incomplete. Numerous studies have focused on the airway epithelium and the neutrophil, yet on the tissue level CF is a lymphocytic disease. Both asthma and allergic bronchopulmonary aspergillosis (ABPA) are commonly found in patients with CF and represent an exuberant CD4 Th2 cell inflammatory response, suggesting that CD4 Th2 cells may be important in CF airway disease as well. Although a number of studies have examined the role of CFTR in airway epithelium, little is known about CFTR function in bone marrow derived cells. Since T lymphocytes express CFTR, they may well be affected by CFTR defects. We have studied the inflammatory response to Aspergillus fumigatus hyphal antigens in the CF airway using two different murine models of CF (delta F508 and CFTR knock out). In both animals we have found that compared to wild type, CF mice (delta F508 and CFTR knock out) generate excessive airway inflammation in response to A. fumigatus exposure. This inflammatory response is characterized by airway eosinophilia and epithelial mucus hypersecretion. In addition, CD4 T cells from A. fumigatus exposed CF mice (delta F508 and CFTR knock out) produce more interleukin-4 (IL-4) than controls, while CD4 T cells from non-exposed delta F508 and CFTR knock out mice have a spontaneous CD4 Th2 bias following in vitro activation. Together, our studies clearly demonstrate that the absence of functional CFTR results in exaggerated airway inflammation in response to A. fumigatus exposure and this appears to be associated with a Th2 bias. Moreover, they show that CD4 T cells from two different CF murine strains have an inherent CD4 Th2 bias even in the absence of A. fumigatus exposure. Our future focus will be to determine if the Th2 bias arises from a deficit of CFTR on CD4 T cells or if it results from a CFTR deficit in another constituent of the immune system or the from the lung airway environment. We will also investigate if correction of CFTR expression by CD4 T cells resolves excessive airway inflammation in response to A. fumigatus exposure and inherent Th2 bias. In addition we will begin studies to understand the mechanism of how a deficit in CFTR on the CD4 T cell results in increased IL-4 production. Our log term goal is to define how inflammatory cell defects contribute to airway destruction in CF.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。囊性纤维化（CF）是一种常见的、致命的遗传性疾病，其起因于CF跨膜传导调节因子（CFTR）的缺陷。大多数CF患者死于进行性呼吸衰竭，尽管对CF肺病的研究已经超过半个世纪，但我们对其发病机制的认识仍然不完整。许多研究集中在气道上皮和中性粒细胞，但在组织水平CF是一种淋巴细胞疾病。哮喘和过敏性支气管肺曲霉菌病（ABPA）在CF患者中常见，并代表了旺盛的CD 4 Th 2细胞炎症反应，这表明CD 4 Th 2细胞在CF气道疾病中也可能很重要。尽管许多研究已经检查了CFTR在气道上皮中的作用，但对CFTR在骨髓源性细胞中的功能知之甚少。由于T淋巴细胞表达CFTR，它们很可能受到CFTR缺陷的影响。 我们使用两种不同的CF小鼠模型（Δ F508和CFTR敲除）研究了CF气道中对烟曲霉菌丝抗原的炎症反应。在这两种动物中，我们发现与野生型相比，CF小鼠（Δ F508和CFTR敲除）响应于A.烟毒暴露这种炎症反应的特征是气道嗜酸性粒细胞增多和上皮粘液分泌过多。此外，A.暴露于烟曲霉的CF小鼠（Δ F508和CFTR敲除）比对照产生更多的白细胞介素-4（IL-4），而来自未暴露的Δ F508和CFTR敲除小鼠的CD 4 T细胞在体外活化后具有自发的CD 4 Th 2偏好。 总之，我们的研究清楚地表明，功能性CFTR的缺乏导致对A.烟曲霉暴露，这似乎与Th 2偏倚有关。此外，他们表明，来自两种不同CF鼠株的CD 4 T细胞具有固有的CD 4 Th 2偏好，即使在不存在A.烟毒暴露我们未来的重点将是确定Th 2偏倚是否源于CD 4 T细胞上CFTR的缺陷，或者是否源于免疫系统另一组成部分的CFTR缺陷或来自肺气道环境。我们还将研究CD 4 T细胞对CFTR表达的纠正是否能缓解A.烟曲霉菌暴露和固有的Th 2偏倚。此外，我们将开始研究以了解CD 4 T细胞上CFTR缺陷如何导致IL-4产生增加的机制。我们的对数期目标是确定炎性细胞缺陷如何导致CF的气道破坏。