Fungal suppression by bacterial metabolite-activated human intestinal γδT-cells is disrupted in Crohn’s disease

Mathew, Liya, Carlson, Sean L., Savage, Michael, Pardieu, Claire, O’Brien, Megan B., Crawley, Ellie, Harrow, Paul, Kaune, Ann-Kristin, Devlin, Edward, Priest, Emily L., Crescente, Marilena, Martinod, Kimberly, Boot, James, Ngan, SoFong Cam, Gasparetto, Marco, Kok, Klaartje, Lindsay, James O., Richardson, Jonathan P., Naglik, Julian R., Stagg, Andrew J., Eberl, Matthias ORCID: https://orcid.org/0000-0002-9390-5348, Sze, Siu Kwan, Munro, Carol A. and McCarthy, Neil E. 2026. Fungal suppression by bacterial metabolite-activated human intestinal γδT-cells is disrupted in Crohn’s disease. PLoS Biology 24 (11) , e3004080. 10.1371/journal.pbio.3004080

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Abstract

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 Candida albicans 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 C. albicans strains that formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1β release ex vivo. Genomic and proteomic analysis of the Candida 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Public Library of Science
ISSN:	1544-9173
Date of First Compliant Deposit:	4 November 2026
Date of Acceptance:	13 October 2026
Last Modified:	04 Nov 2026 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/190665

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