Oral epithelial IL-22/STAT3 signaling licenses IL-17–mediated immunity to oral mucosal candidiasis

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Science Immunology  05 Jun 2020:
Vol. 5, Issue 48, eaba0570
DOI: 10.1126/sciimmunol.aba0570

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Effective immune defense against invasive oral infections by the fungus Candida albicans relies heavily on the cytokine IL-17A and its ability to stimulate a coordinated antifungal response by the multilayered oral epithelium. Aggor et al. used a mouse model of oral candidiasis to investigate the contribution of IL-22, another cytokine produced by many type 17 lymphocytes, to antifungal immunity. The rapid induction of IL-22 after oral Candida infection enhanced IL-22–dependent proliferation of the basal epithelial layer, thereby sustaining the ability of suprabasal epithelial cells expressing IL-17 receptors to respond to IL-17A with induction of immune effectors capable of repelling fungal infection. These findings provide new mechanistic insights into the cooperative antifungal effects of IL-22 and IL-17A in defending the host against oral candidiasis.


Oropharyngeal candidiasis (OPC; thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. Interleukin-17 (IL-17) and IL-22 are cytokines produced by type 17 lymphocytes. Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far less well delineated. We show that, despite having similar requirements for induction from type 17 cells, IL-22 and IL-17 function nonredundantly during OPC. We find that the IL-22 and IL-17 receptors are required in anatomically distinct locations within the oral mucosa; loss of IL-22RA1 or signal transducer and activator of transcription 3 (STAT3) in the oral basal epithelial layer (BEL) causes susceptibility to OPC, whereas IL-17RA is needed in the suprabasal epithelial layer (SEL). Transcriptional profiling of the tongue linked IL-22/STAT3 not only to oral epithelial cell proliferation and survival but also, unexpectedly, to driving an IL-17–specific gene signature. We show that IL-22 mediates regenerative signals on the BEL that replenish the IL-17RA–expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17 and thus to mediate antifungal events. Consequently, IL-22 signaling in BEL “licenses” IL-17 signaling in the oral mucosa, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis.

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