CD4 T CELLS: LESSONS LEARNED FROM ASTHMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。囊性纤维化（CF）是一种常见的致命性遗传疾病，由CF跨膜传导调节因子（CFTR）缺陷引起。大多数CF患者死于进行性呼吸衰竭，尽管对CF肺病的研究已经进行了半个多世纪，但我们对其发病机制的了解仍然不完整。大量的研究集中在气道上皮和中性粒细胞上，但在组织水平上CF是一种淋巴细胞疾病。哮喘和过敏性支气管肺曲霉病（ABPA）常见于CF患者，并表现出旺盛的CD4 Th2细胞炎症反应，提示CD4 Th2细胞可能在CF气道疾病中也很重要。尽管许多研究已经检测了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（delta F508和CFTR敲除）研究了CF气道中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）对烟曲霉暴露产生过度的气道炎症。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，烟曲霉暴露的CF小鼠（delta F508和CFTR敲除）的CD4 T细胞比对照组产生更多的白细胞介素-4 (IL-4)，而未暴露的delta F508和CFTR敲除小鼠的CD4 T细胞在体外激活后会自发地产生CD4 Th2偏倚。总之，我们的研究清楚地表明，缺乏功能性CFTR会导致烟曲霉暴露后气道炎症加剧，这似乎与Th2偏倚有关。此外，他们表明，来自两种不同CF小鼠菌株的CD4 T细胞即使在没有烟曲霉暴露的情况下也具有固有的CD4 Th2偏倚。我们未来的重点将是确定Th2偏倚是由CD4 T细胞上CFTR的缺陷引起的，还是由免疫系统其他成分的CFTR缺陷或肺气道环境引起的。我们还将研究CD4 T细胞纠正CFTR表达是否能解决烟曲霉暴露和固有Th2偏倚导致的气道过度炎症。此外，我们将开始研究了解CD4 T细胞CFTR缺陷如何导致IL-4产生增加的机制。我们的长期目标是确定炎症细胞缺陷如何导致CF患者气道破坏。

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.