Thursday, April 25, 2024
4/25/2024
¿ 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.
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