Fungal suppression by bacterial metabolite-activated human intestinal γδT-cells is disrupted in Crohn’s disease
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.
Authors
- Matthias Eberl (ORCID: https://orcid.org/0000-0002-9390-5348)
- Marco Gasparetto (ORCID: https://orcid.org/0000-0002-3882-3606)
- Julian R. Naglik (ORCID: https://orcid.org/0000-0002-8072-7917)
- Edward Devlin
- Ann-Kristin Kaune (ORCID: https://orcid.org/0000-0002-7157-6360)
- Ellie Crawley
- Emily L. Priest (ORCID: https://orcid.org/0000-0002-4307-7177)
- Paul Harrow (ORCID: https://orcid.org/0000-0002-6819-6623)
- Megan B. O’Brien (ORCID: https://orcid.org/0000-0002-4679-1392)
- Carol A. Munro (ORCID: https://orcid.org/0000-0003-0761-1755)
- James Oliver Lindsay (ORCID: https://orcid.org/0000-0003-3353-9590)
- Marilena Crescente (ORCID: https://orcid.org/0000-0003-3164-512X)
- Neil E. McCarthy (ORCID: https://orcid.org/0000-0002-4330-4747)
- Claire Pardieu (ORCID: https://orcid.org/0000-0003-4257-3811)
- Andrew J. Stagg (ORCID: https://orcid.org/0000-0001-6588-0844)
- James R. Boot (ORCID: https://orcid.org/0000-0002-5629-5026)
- Kimberly Martinod (ORCID: https://orcid.org/0000-0002-1026-6107)
- Sean Carlson (ORCID: https://orcid.org/0009-0003-8222-535X)
- Liya Mathew
- Siu Kwan Sze
- Michael Savage
- SoFong Cam Ngan
- Klaartje Kok
Institutions
- Queen Mary University of London (GB)
- King's College London (GB)
- Brock University (CA)
- University of Aberdeen (GB)
- Barts Health NHS Trust (GB)
- Royal London Hospital (GB)
- University of Rochester Medical Center (US)
- Blizard Institute (GB)
- University of Rochester (US)
- University of Reading (GB)
- Cardiff University (GB)
Publication Details
- Journal
- PLoS Biology
- Published
- 2026-11-02
- DOI
- https://doi.org/10.1371/journal.pbio.3004080
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Barts Charity
- HORIZON EUROPE Framework Programme
- Medical Research Council
- Biotechnology and Biological Sciences Research Council