Dual GM-CSF and IL-17A expressing CD8+ T cells mediate vaccine-immunity, but not immunopathology, against lethal fungal pneumonia in CD4+ T-cell deficient hosts

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Abstract Opportunistic fungal infections are rising at alarming rates in immunocompromised individuals. There is no licensed fungal vaccine available, nor there a clear understanding of the protective host responses. In a mouse model of fungal vaccine-immunity in CD4+ T-cell lymphopenia, we have previously shown that vaccine-induced IL-17A producing CD8+ T (Tc17) cells are necessary for controlling lethal fungal pneumonia. However, we found a significant number of Tc17 cells that co-expressed GM-CSF (>50%), but their role has been implicated as ‘pathogenic’ in autoimmune disorders. In this study, using state-of-the-art approaches, we found that GM-CSF +Tc17 cells are essential for vaccine-immunity against lethal fungal pneumonia without precipitating an adverse immunopathology. Induction of GM-CSF+Tc17 cells, following vaccination, required signaling from cytokines, IL-1 and IL-23, that promoted differentiation and proliferation of effectors. Unexpectedly, IL-23 was dispensable for memory homeostasis of GM-CSF+Tc17 cells. Following the lethal pulmonary fungal challenge, IL-23 was required for the GM-CSF+Tc17 cells responses, but not for their re-differentiation, and was necessary to mitigate the immunopathology of the lungs. Collectively, GM-CSF+Tc17 cells are required for vaccine-mediated immunity against lethal fungal pneumonia.