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 5

Th17 cells mediate vaccine immunity to multiple dimorphic fungi.

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Th17 cells mediate vaccine immunity to multiple dimorphic fungi. (A–D) C...
(A–D) C. posadasii. C57BL/6 mice were vaccinated with the live attenuated strain (ΔT) and challenged with C. posadasii spores as in Methods. The phenotype of lung CD4 T cells was analyzed serially after infection (A and B). IL-17 production by splenocytes in response to T27K Ag was analyzed in vitro as in Methods (C); *P < 0.05 versus respective PBS control (A–C). Vaccinated mice were challenged and lung CFU analyzed 2 weeks after infection (D). The numbers shown are fold reduction in CFU versus respective control. *P < 0.001 versus unvaccinated controls; **P < 0.05 versus vaccinated wild-type mice; ***P < 0.05 versus vaccinated Il17a–/– mice. (E) H. capsulatum. Balb/C and C57BL/6 mice were vaccinated s.c. and challenged with a sublethal dose of H. capsulatum yeast as in Methods. At day 4 after infection, the percentages of IL-17– and IFN-γ–producing CD4+ T cells were assayed by intracellular cytokine staining and FACS. Data are the mean ± SEM of 4 mice/group. *P < 0.01 versus unvaccinated mice; **P < 0.01 versus vaccinated wild-type mice. (F) C57BL/6 wild-type, Il17ra–/–, and Il17a–/– mice were vaccinated and challenged as in Methods. At day 14 after infection, the mice were sacrificed and analyzed for the burden of lung infection. Data are the mean ± SEM of 10 to 20 mice per group. *P < 0.01 versus unvaccinated mice; **P < 0.01 versus vaccinated wild-type mice.