Antigen-restricted Candida albicans Th17 cells link oral-gut immunity and adopt pathogenic features during intestinal inflammation

The commensal yeast Candida albicans is a major inducer of human Th17 cells. How C. albicans drives Th17 responses at homeostasis, and whether such responses contribute to inflammatory diseases, remains poorly understood. Here, we show that C. albicans-reactive Th17 cells exhibit a surprisingly narrow antigen-specificity, targeting a limited set of proteins enriched in fungal extracellular vesicles. At homeostasis, these cells predominantly reside in the oral mucosa. T cell receptor profiling reveals shared clonotypes across oral and gut tissues with C. albicans emerging as the major driver of this repertoire overlap. In Crohn’s disease (CD), C. albicans-specific Th17 cells with features of oral priming are enriched in intestinal tissues where they retain specificity for the same protein targets but acquire pathogenic Th17 traits. Together, our results reveal a stable, antigen-restricted C. albicans Th17 response shared across mucosal sites that undergoes functional adaptation in the inflamed intestine, thus representing a novel target for immune modulation in CD.