Abstract
Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. Here we show that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling are dependent on interleukin-22 and signal transducer and activator of transcription 3 signaling, through a non-canonical receptor complex composed of glycoprotein 130 coupled with the interleukin-22 receptor subunit alpha-1 and the interleukin-10 receptor subunit beta. Epithelial proliferation enhanced antifungal host defenses through the upregulation of antimicrobial peptide expression. Immunosurveillance-induced epithelial remodeling is restricted to the oral mucosa, whereas barrier architecture is reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.
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The authors declare that the data supporting the findings of this study are available within the paper and the accompanying supplementary information files. Source data are provided with this paper. The high-throughput sequencing data from this study have been deposited with links to BioProject accession number PRJNA1176644 in the NCBI BioProject database https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1176644. Source data are provided with this paper.
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Acknowledgements
We thank Jay K. Kolls (Tulane University) for providing the Il22ra1E2a-cre mice, Salomé LeibundGut-Landmann (University of Zurich) for the Candida albicans commensal-like strain CA101, James G. Rheinwald (Dana-Farber/Harvard Cancer Center) for providing the OKF6/TERT-2 cell line, and members of the Division of Infectious Diseases at Harbor-UCLA Medical Center for critical suggestions. NIH grant R01DE031382, R21AI187999 (M.S.), R01AI177254 (S.G.F.), U19AI172713 (M.S., S.G.F.), R21AI159221, R56AI175328 (N.J.), F32AI186291 (M.E.C.), R01AI134796 (B.M.P.), R37DE022550 (S.L.G.), Division of Intramural Research of the NIAID (M.S.L.), California Institute for Regenerative Medicine Stem Cell Biology Training Grant EDUC4-12837 (N.M.).
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Conceptualization: M.S. Methodology: N.M., J.S., N.S., A.M., F.A., A.W., M.E.C., A.D., B.M.P., M.S.L., S.L.G., N.J., S.G.F., M.S. Investigation: N.M., J.S., N.S., J.M., A.M., F.A., A.W., M.S. Visualization: N.M., J.S., F.A., A.W., M.S. Funding acquisition: N.M., M.E.C., N.J., B.M.P., S.L.G., S.G.F., M.S. Project administration: M.S. Supervision: M.S. Writing – original draft: M.S. Writing – review & editing: N.M., J.S., N.S., J.M., A.M., F.A., A.W., M.S.L., B.M.P., S.L.G., N.J., S.G.F., M.S.
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Millet, N., Sekar, J., Solis, N.V. et al. Non-canonical IL‑22 receptor signaling remodels the oral mucosal barrier during Candida albicans immunosurveillance. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71459-z
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DOI: https://doi.org/10.1038/s41467-026-71459-z
