Role of GM-CSF+IL-17+ CD8+ T Cells in Respiratory Fungal Immunity

 描述(由申请人提供)：这项探索性的R21赠款的目的是调查GM-CSF和IL-17双重产生的CD8+T细胞对于疫苗诱导的针对呼吸道真菌感染的免疫是必需的这一概念。免疫功能低下的患者，特别是艾滋病患者的真菌感染急剧增加。CD4+T细胞是抗真菌感染的主要效应者。因此，机会性和原发真菌感染主要发生在CD4+T细胞缺陷的受试者也就不足为奇了。然而，我们之前在疫苗诱导的缺乏CD4+T细胞的真菌免疫小鼠模型中的研究表明，CD8+T细胞的记忆性保持不变，没有明显的数量或功能损失，即细胞因子的产生，这表明在高危个体中利用CD8+T细胞的残余免疫是一种潜在的途径。此外，我们还发现，来自CD8+T细胞的细胞因子，尤其是GM-CSF和IL-17，是介导真菌免疫所必需的，尽管我们还不知道GM-CSF+IL-17A+T细胞的发育和功能。虽然在疫苗诱导的针对病原体的免疫(包括呼吸道感染)中需要产生多种细胞因子的记忆CD8+T细胞，但最近在其他模型中的研究支持了GM-CSF+Th17细胞在中枢神经系统炎症中的致病作用。因此，在呼吸道真菌感染过程中，了解疫苗诱导的致病(GM-CSF+)Th17或Tc17细胞是否介导了有效的免疫或导致免疫病理的活跃反应是至关重要的。填补这一空白将有助于我们理解设计预防感染的疫苗和/或佐剂，并减轻感染期间的免疫病理学。这个探索性的R21方案的目的是描述GM-CSF+Tc17细胞在肺部真菌感染过程中的发育、维持和功能。我们推测，GM-CSF+Tc17细胞是有效的抗真菌免疫所必需的，其中，IL-1β信号需要在肺部感染期间产生并重新进入肺内，而IL-23则需要维持其表型，并在肺部感染期间调节GM-CSF+Tc17细胞的功能，从而平衡免疫和免疫病理。本研究的目的是：(1)剖析GM-CSF+Tc17细胞在肺部真菌感染疫苗诱导免疫中的作用；(2)明确IL-1β和IL-23在疫苗诱导真菌免疫过程中对GM-CSF+Tc17细胞产生、维持和回忆反应的动态和不同作用；(3)描述IL-23在肺部感染免疫和免疫病理中的动态变化。我们的工作将揭示GM-CSF+IL-17+T细胞在抵抗真菌感染的免疫中的作用，并在疫苗模型中剖析它们产生和记忆动态平衡所需的细胞因子。

 DESCRIPTION (provided by applicant): The goal of this exploratory R21 grant is to investigate the concept that GM-CSF & IL-17 dual producing CD8+ T cells are necessary for vaccine-induced immunity against respiratory fungal infections. Fungal infections in immunocompromised patients, especially AIDS patients, have skyrocketed. CD4+ T cells are primary effectors against fungal infections. Hence, it is not surprising that both opportunistic an primary fungal infections occur mainly in CD4+ T-cell deficient subjects. However, our previous studies in a mouse model of vaccine-induced fungal immunity that lack CD4+ T cells have shown that memory CD8+ T-cells are maintained without apparent loss of numbers or functions, i.e., cytokine production, suggesting a potential avenue in exploiting residual immunity by CD8+ T cells in at risk individuals. Further, we showed that the cytokines, especially GM-CSF and IL-17, derived from memory CD8+ T cells, are necessary to mediate the fungal immunity, although we do not know the development and function of GM-CSF+IL-17A+ T-cells. While multi-cytokine producing memory CD8+ T cells are desired in vaccine-induced immunity against pathogens including in respiratory infections, recent studies in other models have underpinned the pathogenic role of GM-CSF+ Th17 cells during central nervous system inflammations. Thus, it is essential to understand whether vaccine-induced `pathogenic (GM-CSF+)' Th17 or Tc17 cells mediate effective immunity or exuberant responses leading to immunopathology during the respiratory fungal infections. Filling this gap would aid in our understanding in designing vaccines and/or adjuvants against infections and mitigate immunopathology during infections. The goal of this exploratory R21 proposal is to delineate the development, maintenance and function of GM-CSF+ Tc17 cells during pulmonary fungal infections. We hypothesize that GM-CSF+ Tc17 cells are necessary for effective anti-fungal immunity where, IL-1 beta signaling is required for their generation and recall into the lungs during pulmonary infections, whereas IL-23 is required to maintain their phenotype and also acts as `rheostat' to regulate GM-CSF+ Tc17 cell functions during pulmonary infections thus balancing immunity and immunopathology. Objectives of our present proposal are: (i) to dissect the role of GM-CSF+ Tc17 cells in vaccine-induced immunity during pulmonary fungal infections; (ii) to define the dynamic and distinct roles of IL- 1beta and IL-23 for generation, maintenance, and recall responses of GM-CSF+ Tc17 cells during vaccine- induced fungal immunity; (iii) to delineate dynamics of IL-23 during pulmonary infection in immunity and immunopathology. Our work will unravel the role of GM-CSF+IL-17+ T cells in immunity against fungal infections and dissect the cytokine requirements for their generation and memory homeostasis in a vaccine model.