Bacterial suppression of intestinal fungi via activation of human gut γδ T-cells

Mathew, L.; Carlson, S.; Savage, M.; Pardieu, C.; O'Brien, M.; Crawley, E.; Harrow, P.; Kaune, A.-K.; Devlin, E.; Priest, E. L.; Crescente, M.; Martinod, K.; Boot, J.; Gasparetto, M.; Kok, K.; Lindsay, J. O.; Richardson, J. P.; Naglik, J. R.; Stagg, A. J.; Eberl, M.; Sze, N.; Munro, C.; McCarthy, N. E.

doi:10.1101/2025.09.17.676560

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bioRxiv · 10.1101/2025.09.17.676560

Bacterial suppression of intestinal fungi via activation of human gut γδ T-cells

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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 V{gamma}9V{delta}2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated V{delta}2+T-cells restricted outgrowth of keystone fungus Candida albicans via a mechanism that required IL-22. In contrast, Crohns disease (CD) patients with reduced V{delta}2+T-cell numbers displayed outgrowth of C. albicans strains that readily formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1{beta} 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 V{delta}2+T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.

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Mathew, L., Carlson, S., Savage, M., Pardieu, C., O'Brien, M., Crawley, E., Harrow, P., Kaune, A.-K., Devlin, E., Priest, E. L., Crescente, M., Martinod, K., Boot, J., Gasparetto, M., Kok, K., Lindsay, J. O., Richardson, J. P., Naglik, J. R., Stagg, A. J., Eberl, M., Sze, N., Munro, C., McCarthy, N. E.. 2025-09-20. Bacterial suppression of intestinal fungi via activation of human gut γδ T-cells. https://doi.org/10.1101/2025.09.17.676560

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