Combination adjuvants drive long-lived plastic Th17 cells that convert to multi-functional Th1 cells and protect mice against fungal infection.

Th1 cells are viewed as a cornerstone of immunity to fungi and other intracellular pathogens. Despite the widely accepted role of Th1 cells in antifungal resistance, the development of protective strategies harnessing them is stunted by a limited understanding of how best to promote their development. We and others have reported a requisite role for Th17 cells in resistance to fungi. We have long been puzzled about how to reconcile seminal roles for both Th1 and Th17 subsets. Here, we report that Th17 cells convert into polyfunctional Th1 cells producing multiple cytokines, including IFN-γ, TNF, and GM-CSF, when we used adjuvant formulations that include glucopyranosyl lipid adjuvant (GLA) to enhance antifungal immunity. GLA-induced plastic Th17 cells that convert into polyfunctional Th1 memory cells.IMPORTANCEVaccines have furnished major improvements in public health worldwide. An understanding of the immune mechanisms that underpin the development of vaccines and strategies to improve them thus represents important goals. We employed a mouse model of blastomycosis to study an experimental vaccine against the causative fungus Blastomyces dermatitidis. By using a protein antigen-based vaccine, we protected the animals against experimental infection. Analysis of the types of cells and features of immunity that shaped vaccine immunity revealed that the cells are ideally endowed with the capacity to protect when they are "polyfunctional"; that is, they evolve to produce several protein products-cytokines-that recruit and activate other immune cells. We found that we could optimally induce polyfunctional cells by adding a special adjuvant, or vaccine enhancer, to the vaccine antigen. Our results establish an important role for the adjuvant and polyfunctional cells in promoting effective vaccination.