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R21资助的目标是研究GM-CSF和IL-17双重产生的CD 8 + T细胞对于疫苗诱导的抗呼吸道真菌感染免疫是必要的。免疫功能低下患者，特别是艾滋病患者的真菌感染急剧增加。CD 4 + T细胞是抗真菌感染的主要效应细胞。因此，机会性和原发性真菌感染主要发生在CD 4 + T细胞缺陷受试者中并不奇怪。然而，我们先前在缺乏CD 4 + T细胞的疫苗诱导的真菌免疫的小鼠模型中的研究已经表明，记忆性CD 8 + T细胞被维持而没有明显的数量或功能损失，即，细胞因子的产生，这表明了在风险个体中利用CD 8 + T细胞的残余免疫的潜在途径。此外，我们发现，细胞因子，特别是GM-CSF和IL-17，来自记忆CD 8 + T细胞，是必要的，介导真菌免疫，虽然我们不知道的发展和功能的GM-CSF+IL-17 A + T细胞。虽然在疫苗诱导的针对病原体（包括呼吸道感染）的免疫中需要产生多细胞因子的记忆性CD 8 + T细胞，但最近在其他模型中的研究已经证实了GM-CSF+ Th 17细胞在中枢神经系统炎症期间的致病作用。因此，了解疫苗诱导的“致病性（GM-CSF+）”Th 17或Tc 17细胞是否介导有效免疫或导致呼吸道真菌感染期间免疫病理学的旺盛应答是至关重要的。填补这一空白将有助于我们理解设计疫苗和/或佐剂对抗感染和减轻感染期间的免疫病理学。这项探索性R21提案的目标是描述肺部真菌感染期间GM-CSF+ Tc 17细胞的发育、维持和功能。我们假设GM-CSF+ Tc 17细胞对于有效的抗真菌免疫是必需的，其中在肺部感染期间，IL-1 β信号传导是它们的产生和被召回到肺部所必需的，而IL-23是维持它们的表型所必需的，并且在肺部感染期间还充当调节GM-CSF+ Tc 17细胞功能的“变阻器”，从而平衡免疫和免疫病理学。本研究的目的是：（i）分析GM-CSF+ Tc 17细胞在肺部真菌感染疫苗诱导免疫中的作用;（ii）确定IL-1 β和IL-23在疫苗诱导真菌免疫过程中对GM-CSF+ Tc 17细胞产生、维持和回忆应答的动态和不同作用;（3）探讨IL-23在肺部感染过程中的动态变化及其免疫病理学意义。 我们的工作将揭示GM-CSF+IL-17+ T细胞在抗真菌感染免疫中的作用，并在疫苗模型中剖析其产生和记忆稳态的细胞因子需求。

 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.