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Selection of cross-reactive T cells by commensal and food-derived yeasts drives pathogenic cytotoxic Th1 responses in Crohn´s disease

ABSTRACT: Selection of cross-reactive T cells by commensal and food-derived yeasts drives pathogenic cytotoxic Th1 responses in Crohn´s disease

PROVIDER: PRJNA946136 | ENA |

REPOSITORIES: ENA

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Selection of cross-reactive T cells by commensal and food-derived yeasts drives pathogenic cytotoxic Th1 responses in Crohn´s disease

Project description:Aberrant CD4+ T cell reactivity against intestinal microbes is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microbe-specific pathogenic T cell phenotypes remain unknown. Here, we identify common gut commensal and food-derived yeasts, as direct activators of aberrant CD4+ T cell reactions in patients with Crohn´s disease (CD). Yeast-responsive CD4+ T cells in CD display a cytotoxic Th1 phenotype and selective clonal expansion of cells 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 highlight a role of fungi in driving immunopathology in patients with CD and suggest that both, gut-resident fungal commensals, and daily dietary intake of yeasts, may contribute to chronic activation of pathogenic CD4+ T cell responses involved in disease pathophysiology.

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Project description:Purpose: To clarify the biological processes underlying variation in disease location and antimicrobial sero-reactivity across age-of onset in pediatric Crohn disease. Methods: We characterize the ileal global pattern of gene expression using single-end, 50bp RNA-sequencing using the Illumina HiSeq2000 in 304 treatment-naïve pediatric Crohn patients and non-IBD controls. Reads were quantified using Kallisto with Gencodev23 annotations. For all analyses, data were stratified by patient age-of-onset. Results: Performing differential analysis of all reasonably-expressed transcripts (TPM>5 in ≥5 samples, with significance defined as FDR-corrected p-value<0.05 and fold change≥1.5), we identify a robust gene signature with higher expresison of an immune gene set in older patients (≥10 years at diagnosis) compared to younger patients (<10 years at diagnosis), and a decrease in expression of antimicrobial Paneth cell-derived α-defensins. Conclusion: We provide evidence for maturation of mucosal Th1 immune response and loss of epithelial antimicrobial α-defensins with increasing age-of-onset.

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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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