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Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic T_H1 cell responses in Crohn's disease.

ABSTRACT: Aberrant CD4⁺ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4⁺ T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4⁺ T cells in CD display a cytotoxic T helper cell (T_H1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4⁺ T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4⁺ T cell responses in patients with CD.

SUBMITTER: Martini GR

PROVIDER: S-EPMC10579100 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn's disease.

Martini Gabriela Rios GR Tikhonova Ekaterina E Rosati Elisa E DeCelie Meghan Bialt MB Sievers Laura Katharina LK Tran Florian F Lessing Matthias M Bergfeld Arne A Hinz Sophia S Nikolaus Susanna S Kümpers Julia J Matysiak Anna A Hofmann Philipp P Saggau Carina C Schneiders Stephan S Kamps Ann-Kristin AK Jacobs Gunnar G Lieb Wolfgang W Maul Jochen J Siegmund Britta B Seegers Barbara B Hinrichsen Holger H Oberg Hans-Heinrich HH Wesch Daniela D Bereswill Stefan S Heimesaat Markus M MM Rupp Jan J Kniemeyer Olaf O Brakhage Axel A AA Brunke Sascha S Hube Bernhard B Aden Konrad K Franke Andre A Iliev Iliyan D ID Scheffold Alexander A Schreiber Stefan S Bacher Petra P

Nature medicine 20230925 10

Aberrant CD4+ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4+ T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4<su ...[more]

PMID: 37749331

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Project description:Prenylated isoflavonoids are phytochemicals with promising antifungal properties. Recently, it was shown that glabridin and wighteone disrupted the plasma membrane (PM) of the food spoilage yeast Zygosaccharomyces parabailii in distinct ways, which led us to investigate further their modes of action (MoA). Transcriptomic profiling with Z. parabailii showed that genes encoding transmembrane ATPase transporters, including Yor1, and genes homologous to the pleiotropic drug resistance (PDR) subfamily in Saccharomyces cerevisiae were upregulated in response to both compounds. Gene functions involved in fatty acid and lipid metabolism, proteostasis, and DNA replication processes were overrepresented among genes upregulated by glabridin and/or wighteone. Chemogenomic analysis using the genome-wide deletant collection for S. cerevisiae further suggested an important role for PM lipids and PM proteins. Deletants of gene functions involved in biosynthesis of very-long-chain fatty acids (constituents of PM sphingolipids) and ergosterol were hypersensitive to both compounds. Using lipid biosynthesis inhibitors, we corroborated roles for sphingolipids and ergosterol in prenylated isoflavonoid action. The PM ABC transporter Yor1 and Lem3-dependent flippases conferred sensitivity and resistance, respectively, to the compounds, suggesting an important role for PM phospholipid asymmetry in their MoAs. Impaired tryptophan availability, likely linked to perturbation of the PM tryptophan permease Tat2, was evident in response to glabridin. Finally, substantial evidence highlighted a role of the endoplasmic reticulum (ER) in cellular responses to wighteone, including gene functions associated with ER membrane stress or with phospholipid biosynthesis, the primary lipid of the ER membrane. IMPORTANCE Preservatives, such as sorbic acid and benzoic acid, inhibit the growth of undesirable yeast and molds in foods. Unfortunately, preservative tolerance and resistance in food spoilage yeast, such as Zygosaccharomyces parabailii, is a growing challenge in the food industry, which can compromise food safety and increase food waste. Prenylated isoflavonoids are the main defense phytochemicals in the Fabaceae family. Glabridin and wighteone belong to this group of compounds and have shown potent antifungal activity against food spoilage yeasts. The present study demonstrated the mode of action of these compounds against food spoilage yeasts by using advanced molecular tools. Overall, the cellular actions of these two prenylated isoflavonoids share similarities (at the level of the plasma membrane) but also differences. Tryptophan import was specifically affected by glabridin, whereas endoplasmic reticulum membrane stress was specifically induced by wighteone. Understanding the mode of action of these novel antifungal agents is essential for their application in food preservation.

Dataset Information

Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic T_H1 cell responses in Crohn's disease.

Publications

Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic T<sub>H</sub>1 cell responses in Crohn's disease.

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