Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all caused by C. albicans species, host defense against C. albicans varies by anatomical location. T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19 ^-/-) and IL-17R-deficient (IL-17RA ^-/-) mice experienced severe OPC, whereas Thl-deficient (IL-12p35 ^-/-) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was impaired in IL-23p19 ^-/- and IL-17RA ^-/-, but not IL-12 ^-/-, mice, and TCR-αβ cells were more important than TCR-7gamma;δ cells. Surprisingly, mice deficient in the Th17 cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong induction of Th17 signature genes, including CXC chemokines and β defen- sin-3. Saliva from Th17-deficient, but not Thl-deficient, mice exhibited reduced candida- cidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.