Immune-epithelial networks characterise the cellular ecosystem of the small intestine in celiac disease

The immune-epithelial interactions driving intestinal damage in coeliac disease (CD) are incompletely understood.We applied single-cell (scRNA-seq) and spatial transcriptomics to define this. scRNA-seq of 76,824 immune and epithelial cells in 23 subjects with and without CD showed epithelial populations shifted towards a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T-cells showed numeric and functional changes in regulatory, T follicular helper-like CD4+T-cell, natural intraepithelial lymphocytes, and CD8+T-cell subsets with a skewed TCR repertoire.Mucosal changes persisted despite treatment, representing a persistent immune-epithelial 'scar'. Spatial transcriptomics defined transcriptionally-distinct niches beyond that described in conventional histological scores,including CD-specific lymphoid structures containing localised T-B cell interactions. Spatial transcriptomics-driven receptor-ligand analyses and examination of disease susceptibility gene expression defined networks of altered chemokine and morphogen signalling, which may drive crypt axis distortion andallowed spatial/cellular resolution of where genetic drivers of CD act in tissue. 10x visium spatial transcriptomics of duodenal biopsies from study subjects with and without celiac disease