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.

Conti et al. show that IL-17 is produced by tongue-resident populations of γδ T cells and nTh17 cells in response to oropharyngeal candidiasis in mice.

SUMMARY Th17 cells and CD4+CD25+Foxp3+ regulatory T (Treg) cells are thought to promote and suppress inflammatory responses, respectively. Here we explore why under Th17 cell conditions, Treg cells did not suppress, but rather up-regulated the expression of interleukin-17A (IL-17A), IL-17F and IL-22 from responding CD4+ cells (Tresp). Up-regulation of IL-17 cytokines in Tresp cells was dependent on consumption of IL-2 by Treg cells especially at early time points both in vitro and in vivo. During an oral Candida albicans infection in mice, Treg cells induced IL-17 cytokines in Tresp cells, which markedly enhanced fungal clearance and recovery from infection. These findings show how Treg cells can promote acute Th17 cell responses to suppress mucosal fungus infections and reveal that Treg cells have a powerful capability to fight infections besides their role in maintaining tolerance or immune homeostasis.

IL-17 (IL-17A) has emerged as a key mediator of protection against extracellular microbes, but this cytokine also drives pathology in various autoimmune diseases. Overwhelming data in both humans and mice reveal a clear and surprisingly specific role for IL-17 in protection against the fungus Candida albicans, a commensal of the human oral cavity, gastrointestinal tract and reproductive mucosa. The IL-17 pathway regulates antifungal immunity through upregulation of pro-inflammatory cytokines including IL-6, neutrophil-recruiting chemokines such as CXCL1 and CXCL5 and antimicrobial peptides such as the defensins, which act in concert to limit fungal overgrowth. This review will focus on diseases caused by C. albicans, the role of IL-17-mediated immunity in candidiasis, and the implications for clinical therapies for both autoimmune conditions and fungal infections.