| Candida albicans is the causative agent of oropharyngeal (OPC), vaginal, gastric and systemic candidiasis. Both innate and adaptive immunity play an overall protective role in C. albicans infection. However, the relative contribution of each branch seems to be "compartment specific", as the importance of CD4+ T cells in OPC is strikingly demonstrated in HIV+ patients that are highly susceptible to OPC, but not to systemic or vaginal candidiasis. Protective adaptive responses in anti-Candida immunity have long been thought to be dominated by Th1-effector cells, while the role of Th17 cells remains controversial. In a gastric model of mucosal candidiasis IL-23 and IL-17 were shown to mediate inflammatory pathology, but were protective in disseminated candidiasis. In this study we compared Th1- and Th17-mediated protective mechanisms in a model of OPC.Th17-deficient (IL-23p19-/-) and IL-17RA-/- mice were highly susceptible to OPC, while Th1-deficient mice (IL-12p35-/-), had low fungal burdens and no overt signs of disease. Mice deficient in TCRalphabeta cells were also susceptible, although mice lacking TCRgammadelta cells and the Th17 cytokine IL-22 were only mildly susceptible to infection. Neutrophil recruitment was also impaired in IL-23p19-/- (IL-23KO), IL-17RA-/- (IL-17RA KO), and IL-17RC-/- (IL-17RCKO), but not IL-12p35-/- (IL-12KO) mice. Microarray analysis of infected wild-type (WT) oral mucosal tissue demonstrated induction of various Th17 signature genes, including antimicrobial peptides such as betadefensin-3. Saliva from Th17-deficient mice showed reduced candidacidal activity compared to saliva from Th1-deficient mice. Salivary gland tissue from IL-23KO mice displayed a unique gene expression profile compared to WT tissue, indicative of a defective salivary gland. Additionally, saliva from Th17-deficient HIES patients demonstrated reduced anticandidal properties due to a deficiency in the antimicrobial proteins, ssdefensin-2 and histatin. Our results indicate that Th17-mediated immunity plays a dominant role in mucosal anti-Candida immunity through the induction of neutrophils and antimicrobial factors, whereas Th1-mediated immunity plays a comparatively minor role in host defense. |
