Characterization of Aspergillus fumigatus specific CD4 T cell responses.

烟曲霉是一种孢子形成霉菌，可引起包括过敏在内的一系列人类疾病。 支气管肺曲霉菌病，一种类似哮喘的疾病，以及侵袭性曲霉菌病，一种经常致命的 发生在免疫受损个体中的感染。由烟曲霉引起的感染是由 吸入真菌孢子(称为分生孢子)，被肺泡巨噬细胞摄取并被 氧化爆发的产物。尽管烟曲霉特异的T淋巴细胞被认为在 过敏性和侵袭性曲霉病，对它们的激活、增殖、分化知之甚少。 以及吸入真菌孢子后的持久性。为了解决这个问题，我们制作了CD4T细胞杂交瘤 针对烟曲霉菌抗原，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。这项拨款申请中提出的实验将使用SET CELL 受体转基因小鼠获得幼稚、烟曲霉菌特异性T细胞用于转移和鉴定 受感染的小鼠。我们有三个具体目标。第一个是研究启动和分化。 活孢子肺部感染后烟曲霉菌特异性T淋巴细胞。II_10的影响 并将确定转化生长因子-β信号对T细胞增殖和分化的影响。第二个目标是 确定烟曲霉特异性CD4T细胞在免疫低下的侵袭性真菌病中的作用 或骨髓移植小鼠。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。我们会 最初专注于MyD88、Trif和RIP2介导的信号。这些研究将提供一个全面的图景 T细胞对人类最常见的机会性真菌病原体的反应，潜在地打开了 与过敏性和侵袭性真菌疾病作斗争的新的治疗措施之门。

Aspergillus fumigatus is a spore forming mould 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 useT 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 naTve A. fumigatus-specific T lymphocytes following pulmonary infection with live conidia. The impact ofii_10 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.