Characterization of Aspergillus fumigatus specific CD4 T cell responses.

烟曲霉是一种形成孢子的霉菌，可引起一系列人类疾病，包括过敏性疾病 支气管肺曲霉病（一种类似哮喘的疾病）和侵袭性曲霉病（一种经常致命的疾病） 发生在免疫功能低下的个体中的感染。烟曲霉感染的原因是 吸入真菌孢子（称为分生孢子），被肺泡巨噬细胞吸收并被杀死 氧化爆发的产物。尽管烟曲霉特异性 T 淋巴细胞被认为在 过敏性和侵袭性曲霉病，人们对它们的激活、增殖和分化知之甚少 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 CD4 T 细胞杂交瘤 对烟曲霉抗原具有特异性，克隆了特定 T 细胞受体的 α 和 β 链， 产生T细胞受体转基因小鼠。本拨款申请中提出的实验将使用 T 细胞 受体转基因小鼠以获得幼稚的烟曲霉特异性 T 细胞，用于转移和表征 感染的受体小鼠。我们有三个具体目标。首先是研究启动和分化 活分生孢子肺部感染后天然烟曲霉特异性 T 淋巴细胞。 ii_10的影响 并确定TGF-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 CD4 T 细胞对免疫功能低下的侵袭性真菌病的影响 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 并确定该过程对烟曲霉特异性 CD4 T 细胞分化的影响。我们会 最初关注 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，可能打开 对抗过敏性和侵袭性真菌疾病的新治疗干预措施的大门。

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.