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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

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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 3

Th1 cells are dispensable in vaccine immunity to fungi.

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Th1 cells are dispensable in vaccine immunity to fungi.
(A) Il12p35–/– a...
(A) Il12p35–/– and Il12/23p40–/–, (B) Il12rb2–/–, (C) Tbet–/–, or (D) Tbet–/–Stat4–/– and wild-type mice were vaccinated and challenged with B. dermatitidis as in Methods and the lung CFU analyzed. CFU values are the mean ± SEM of 10–12 mice/group; representative of 2 experiments per group. The numbers shown are fold reduction in lung CFU versus unvaccinated controls. *P < 0.001 versus unvaccinated controls and vaccinated p40–/– mice. (E) Vaccine-induced Th17 cells do not mediate lung pathology. Histology (16 days after infection) of lungs from wild-type and Th1-deficient vaccinated mice showed normal lung alveolar parenchyma with few foci of perivascular lymphocytes, but no PMN infiltrates. In contrast, lungs from unvaccinated mice showed massive infiltration with PMNs and macrophages and many yeast. Original magnification, ×100; ×400 (insets).

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