Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice
Marcel Wüthrich, … , Garry Cole, Bruce Klein
Marcel Wüthrich, … , Garry Cole, Bruce Klein
Published January 4, 2011
Citation Information: J Clin Invest. 2011;121(2):554-568. https://doi.org/10.1172/JCI43984.
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Research Article

Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice

Abstract

Worldwide rates of systemic fungal infections, including three of the major pathogens responsible for such infections in North America (Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis), have soared recently, spurring interest in developing vaccines. The development of Th1 cells is believed to be crucial for protective immunity against pathogenic fungi, whereas the role of Th17 cells is vigorously debated. In models of primary fungal infection, some studies have shown that Th17 cells mediate resistance, while others have shown that they promote disease pathology. Here, we have shown that Th1 immunity is dispensable and that fungus-specific Th17 cells are sufficient for vaccine-induced protection against lethal pulmonary infection with B. dermatitidis in mice. Further, vaccine-induced Th17 cells were necessary and sufficient to protect against the three major systemic mycoses in North America. Mechanistically, Th17 cells engendered protection by recruiting and activating neutrophils and macrophages to the alveolar space, while the induction of Th17 cells and acquisition of vaccine immunity unexpectedly required the adapter molecule Myd88 but not the fungal pathogen recognition receptor Dectin-1. These data suggest that human vaccines against systemic fungal infections should be designed to induce Th17 cells if they are to be effective.

Authors

Marcel Wüthrich, Benjamin Gern, Chiung Yu Hung, Karen Ersland, Nicole Rocco, John Pick-Jacobs, Kevin Galles, Hanna Filutowicz, Thomas Warner, Michael Evans, Garry Cole, Bruce Klein

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Figure 4

Ag-specific Th17 cells are sufficient to mediate antifungal resistance.

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Ag-specific Th17 cells are sufficient to mediate antifungal resistance. ...
(A) Polarization of Th17 cells. The dot plot shows the percentage of IL-17– and IFN-γ–positive CD4+ cells and is representative of all 4 types of TCR Tg T cells (below). (B and C) Transfer of Th17-polarized cells into wild-type recipients. Th17-polarized cells from wild-type × 1807, Il12rb2–/– × 1807, Tbet–/– × 1807, and OT2 mice were transferred into nonirradiated or sublethally irradiated wild-type mice (78). The next day (nonirradiated recipients) or 8 weeks later (irradiated recipients), mice were challenged with B. dermatitidis and analyzed for lung CFU 2 weeks later. Values are the mean ± SEM (n = 11–18). Numbers shown are fold reduction in lung CFU versus OT2 controls. *P < 0.05 versus OT2 controls. (D) In vivo primed Th17 cells protect vaccinated OT1 mice. 106 wild-type × 1807, Il12rb2–/– × 1807, and Tbet–/– × 1807 cells were transferred into OT1 mice. Recipients were vaccinated, challenged, and analyzed for lung CFU. Values are the mean ± SEM (n = 9–12). Numbers shown are the fold reduction in lung CFU versus OT2 controls. *P < 0.05 versus unvaccinated mice and vaccinated mice that received OT2 cells. (E) T helper phenotype of in vivo primed Il12rb2–/– × 1807 and Tbet–/– × 1807 cells. At day 4 after infection, the percentages of cytokine-producing transferred Tg cells were quantified (4–6 mice per group). *P < 0.05 versus 1807 × Tbet–/– and 1807 × Il12rb2–/– cells. (F) IL-17 and IFN-γ production by splenocytes in response to CW/M Ag in vitro was analyzed; *P < 0.05 versus all other groups.