CD4 T CELLS: LESSONS LEARNED FROM ASTHMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 囊性纤维化是一种常见的致死性遗传病，由囊性纤维化跨膜电导调节蛋白缺陷引起。大多数CF患者死于进行性呼吸衰竭，尽管对CF肺部疾病的研究已有半个多世纪，但我们对其发病机制的了解仍不完整。许多研究都集中在呼吸道上皮细胞和中性粒细胞上，然而在组织水平上，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)均可见于CF患者，表现为活跃的CD4Th2细胞炎症反应，提示CD4Th2细胞可能在CF气道病中也起重要作用。尽管已有多项研究探讨了CFTR在呼吸道上皮细胞中的作用，但对CFTR在骨髓来源细胞中的作用知之甚少。由于T淋巴细胞表达CFTR，它们很可能受到CFTR缺陷的影响。 我们用两种不同的小鼠CF模型(Delta F508和CFTR基因敲除)研究了CF气道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(Delta F508和CFTR基因敲除)在接触烟曲霉菌时会产生过度的呼吸道炎症。这种炎症反应的特征是呼吸道嗜酸性粒细胞增多和上皮性粘液高分泌。此外，暴露于烟曲霉菌的CF小鼠的CD4T细胞(Delta F508和CFTR基因敲除)比对照组产生更多的白介素4(IL-4)，而来自未暴露的Delta F508和CFTR基因敲除小鼠的CD4T细胞在体外激活后有自发的CD4Th2偏向。 总之，我们的研究清楚地表明，功能性CFTR的缺失会导致对烟曲霉菌暴露的过度呼吸道炎症反应，这似乎与Th2偏向有关。此外，他们还表明，即使在没有接触烟曲霉菌的情况下，来自两个不同的CF小鼠品系的CD4T细胞也具有固有的CD4Th2偏向。我们未来的重点将是确定Th2偏向是由CD4T细胞上CFTR的缺陷引起的，还是由免疫系统的另一组分的CFTR缺陷引起的，还是由肺气道环境引起的。我们还将调查CD4T细胞纠正CFTR表达是否能解决因烟曲霉菌暴露和固有的Th2偏向而导致的过度呼吸道炎症。此外，我们将开始研究CD4T细胞CFTR缺陷如何导致IL-4产生增加的机制。我们的对数术语目标是定义炎症细胞缺陷如何促进CF中的呼吸道破坏。

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.