Characterization of Aspergillus fumigatus specific CD4 T cell responses.

描述（由申请方提供）：烟曲霉是一种孢子形成霉菌，可引起一系列人类疾病，包括过敏性支气管肺炎曲霉病（一种哮喘样疾病）和侵袭性曲霉病（一种经常发生在免疫功能低下个体中的致命感染）。烟曲霉的感染是由于吸入真菌孢子（称为分生孢子），这些孢子被肺泡巨噬细胞吸收并被氧化爆发的产物杀死。虽然A.尽管烟曲霉特异性T淋巴细胞被假定在过敏性和侵袭性曲霉病中起作用，但关于它们在吸入真菌孢子后的活化、增殖、分化和持久性知之甚少。为了解决这个问题，我们制备了A.烟曲霉抗原，克隆了特异性T细胞受体的α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获得幼稚的，A。烟曲霉特异性T细胞用于在感染的受体小鼠中转移和表征。我们有三个具体目标。第一部分是研究幼稚A.肺感染活孢子后的烟曲霉特异性T淋巴细胞。将确定IL 10和TGF-β信号传导对T细胞增殖和分化的影响。第二个目的是确定A.烟曲霉特异性CD 4 T细胞对免疫功能低下或骨髓移植小鼠侵袭性真菌病的影响。我们的第三个目标是研究对真菌孢子的先天免疫应答，并确定这一过程对A.烟曲霉特异性CD 4 T细胞。我们将首先关注MyD 88，Trif和Rip 2介导的信号。这些研究将全面了解T细胞对人类最普遍的机会性真菌病原体的反应，可能为对抗过敏性和侵袭性真菌疾病的新治疗干预打开大门。

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.