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.
Fungal infections in immunocompromised patients, especially AIDS patients, have skyrocketed. No licensed fungal vaccines are available. Our work delineates protective immune mechanisms involving CD8+ T cells in a vaccine model. Our work also dissects the translational aspects to design vaccine adjuvants and to prevent overt immunopathology. Knowledge gleaned by our studies would help develop modalities to prevent opportunistic infections.
| Nanjappa, Som G; Mudalagiriyappa, Srinivasu; Fites, J Scott et al. (2018) CBLB Constrains Inactivated Vaccine-Induced CD8+ T Cell Responses and Immunity against Lethal Fungal Pneumonia. J Immunol 201:1717-1726 |
| Nanjappa, Som Gowda; McDermott, Andrew J; Fites, J Scott et al. (2017) Antifungal Tc17 cells are durable and stable, persisting as long-lasting vaccine memory without plasticity towards IFN? cells. PLoS Pathog 13:e1006356 |
