<p>by Liya Mathew, Sean L. Carlson, Michael Savage, Claire Pardieu, Megan B. O’Brien, Ellie Crawley, Paul Harrow, Ann-Kristin Kaune, Edward Devlin, Emily L. Priest, Marilena Crescente, Kimberly Martinod, James Boot, SoFong Cam Ngan, Marco Gasparetto, Klaartje Kok, James O. Lindsay, Jonathan P. Richardson, Julian R. Naglik, Andrew J. Stagg, Matthias Eberl, Siu Kwan Sze, Carol A. Munro, Neil E. McCarthy</p> Gut symbionts condition mucosal immunity to resist infection by enteropathogens, but the specific microbes and mechanisms involved differ significantly between host species. In higher primates, bacterial metabolite HMB-PP is sensed by a specialized population of Vγ9Vδ2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated Vδ2+ T-cells restricted outgrowth of keystone fungus <i>Candida albicans</i> via a mechanism that required IL-22. In Crohn’s disease (CD), Vδ2+ T-cells were poorly responsive to HMB-PP and permitted outgrowth of <i>C. albicans</i> strains that formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1β release <i>ex vivo</i>. Genomic and proteomic analysis of the <i>Candida</i> isolates suggested increased tissue adhesion of CD-derived strains, which rapidly invaded the gut barrier in an ‘intestine-on-a-chip’ model. These data reveal that bacterial activation of Vδ2+ T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.