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 Th1-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-γδ 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 defensin-3. Saliva from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.

Summary: Interleukin‐17 (IL‐17) has emerged as a central player in the mammalian immune system. Although this cytokine exerts a host‐defensive role in many infectious diseases, it promotes inflammatory pathology in autoimmunity and other settings. A myriad of studies have focused on how IL‐17‐producing cells are generated. However, the means by which IL‐17 achieves its effects, either for the benefit or the detriment of the host, are due in large part to the induction of new gene expression. Whereas many IL‐17 target genes are common to different disease states, in some cases the effects of IL‐17 differ depending on the target cell, infectious site or pathogen. Gene products induced by IL‐17 include cytokines (IL‐6, granulocyte‐colony‐stimulating factor, tumour necrosis factor‐α), chemokines (CXCL1, CXCL2, CCL20, among many others), inflammatory effectors (acute‐phase protesins, complement) and antimicrobial proteins (defensins, mucins). Different cell types appear to respond differently to IL‐17 in terms of target gene expression, with notable differences seen in mesenchymal and epithelial cells compared with cells of haematopoietic origin. Here, we summarize the major IL‐17 target genes that mediate this cytokine’s activities in both autoimmune and chronic diseases as well as during various types of infections.