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 1

Naive CD4 T cells differentiate into Th17 cells during the afferent phase of vaccination and are recalled to the lung during the efferent phase.

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Naive CD4 T cells differentiate into Th17 cells during the afferent phas...
(A) Ag-specific Th17 cells accumulate in the skin-draining lymph nodes during vaccine induction. Purified CD4 T cells from the skin-draining lymph nodes of vaccinated mice were cocultured with CW/M Ag for 2 days and cytokine transcripts analyzed by RT-PCR. Mean ± SEM (n = 3); representative of 3 experiments. (B) Primed Th17 cells produce IL-17 in response to in vitro Ag stimulation. 3 weeks after the boost, purified CD4 T cells from the draining nodes were stimulated with CW/M Ag for 3 days and the supernatants analyzed. Mean ± SEM (n = 4); representative of 3 experiments. (C) Th17 cells infiltrate the vaccine site. Lymphocytes were isolated from the vaccine site. To verify cytokine response by Ag-specific T cells, B. dermatitidis–specific 1807 Tg cells were transferred into recipients before vaccination. T cells from the site were stimulated with α-CD3 and α-CD28 mAb for 4 hours and analyzed for intracellular cytokine. Dot plots show percentage of cytokine-producing polyclonal or Tg CD4 cells. (D and E) Th17 effector cells migrate to the lung during the recall and vaccine efferent phase. Vaccinated mice were challenged with B. dermatitidis i.t. and the expression of lung cytokine transcript was measured by RT-PCR. For the kinetics of IL-17– and IFN-γ– producing CD4 T cells, the number of cytokine-producing cells was calculated by multiplying the number of total lung cells by the percentage of cytokine-producing CD4 T cells. Mean ± SEM (n = 4); representative of 3 experiments. (F) Lung CFUs coincide with number of cytokine-producing CD4 T cells. Mean ± SEM (n = 8–10); representative of 2 experiments. *P < 0.05 versus unvaccinated mice.