Characterization of Aspergillus fumigatus specific CD4 T cell responses.

描述(由申请人提供)：烟曲霉是一种孢子形成霉菌，可导致一系列人类疾病，包括过敏性支气管肺曲霉菌病，一种哮喘样疾病，以及侵袭性曲霉病，一种经常发生在免疫功能低下的人身上的致命感染。感染烟曲霉菌的原因是吸入了真菌孢子(称为分生孢子)，分生孢子被肺泡巨噬细胞摄取，并被氧化爆发的产物杀死。尽管烟曲霉菌特异性T淋巴细胞在过敏性和侵袭性曲霉病中都起作用，但对其在吸入真菌孢子后的激活、增殖、分化和持久性了解甚少。为了解决这个问题，我们制作了针对烟曲霉菌抗原的CD4T细胞杂交瘤，克隆了特异性T细胞受体的α链和β链，并产生了T细胞受体转基因小鼠。在这项拨款申请中提出的实验将使用T细胞受体转基因小鼠来获得幼稚的、烟曲霉菌特异的T细胞，用于在受感染的小鼠中转移和鉴定。我们有三个具体目标。第一个是研究活孢子肺部感染后幼稚烟曲霉菌特异性T淋巴细胞的启动和分化。IL-10和转化生长因子-β信号对T细胞增殖和分化的影响将被确定。第二个目的是确定烟曲霉特异的CD4T细胞对免疫受损或骨髓移植小鼠侵袭性真菌疾病的影响。我们的第三个目标是研究对真菌孢子的先天免疫反应，并确定这一过程对烟曲霉特异性CD4T细胞分化的影响。我们将首先关注MyD88、Trif和RIP2介导的信号。这些研究将提供T细胞对人类最普遍的机会性真菌病原体的反应的全面图景，可能为对抗过敏性和侵袭性真菌疾病的新的治疗干预打开大门。

DESCRIPTION (provided by applicant): Aspergillus fumigatus is a spore forming mold that causes a range of human diseases, including allergic bronchopulmonary aspergillosis, an asthma-like disease, and invasive aspergillosis, a frequently fatal infection that occurs in immunocompromised individuals. Infection by Aspergillus fumigatus results from inhalation of fungal spores (referred to as conidia), which are taken up by alveolar macrophages and killed by products of the oxidative burst. Although A. fumigatus-specific T lymphocytes are postulated to play a role in both allergic and invasive aspergillosis, very little is known about their activation, proliferation, differentiation and persistence following inhalation of fungal spores. To address this issue, we made CD4 T cell hybridomas specific for A. fumigatus antigens, cloned the alpha and beta chains of the specific T cell receptor and generated T cell receptor transgenic mice. Experiments proposed in this grant application will use T cell receptor transgenic mice to obtain naive, A. fumigatus-specific T cells for transfer and characterization in infected recipient mice. We have three specific aims. The first is to investigate priming and differentiation of naive A. fumigatus-specific T lymphocytes following pulmonary infection with live conidia. The impact of IL10 and TGF-beta signaling on T cell proliferation and differentiation will be determined. The second aim is to determine the impact of A. fumigatus-specific CD4 T cells on invasive fungal disease in immunocompromised or bone marrow transplanted mice. Our third aim is to investigate innate immune responses to fungal spores and to determine the impact of this process on the differentiation of A. fumigatus-specific CD4 T cells. We will initially focus on MyD88, Trif and Rip2 mediated signals. These studies will provide a comprehensive picture of T cell responses to the most prevalent opportunistic fungal pathogen of humans, potentially opening the door to new therapeutic interventions to combat allergic and invasive fungal diseases.