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A human autoimmune organoid model reveals IL-7 function in celiac disease

ABSTRACT: In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Celiac disease (CeD) is an autoimmune disease where dietary gluten-derived peptides bind the MHC- II molecules HLA-DQ2 or -DQ8 to initiate immune-mediated duodenal mucosal injury. Here, we generated air-liquid interface (ALI) duodenal organoids from endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The ALI organoid immune diversity spanned T, B, plasma, NK and myeloid cells with extensive T and B cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing CeD patient organoids, which was antagonized by MHC-II or NKG2C/D blockade. Gluten epitopes stimulated a CeD organoid network response in lymphoid and myeloid subsets alongside anti-TG2 autoantibody production. Functional studies in CeD organoids revealed IL-7 as a novel gluten-inducible pathogenic modulator which regulated CD8+ T cell-NKG2C/D expression and was necessary and sufficient for epithelial destruction. Further, endogenous IL-7 was markedly induced in patient biopsies from active CeD versus remission disease, predominantly in lamina propria mesenchyme. By preserving epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, facilitates mechanistic investigation, and establishes proof-of-principle for organoid modeling of autoimmunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200075 | GEO | 2024/07/12

REPOSITORIES: GEO

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Project description:Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gâproducing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases. Experiment Overall Design: Using a standard GeneChip preparation protocol (Affymetrix, Santa Clara CA), gene array hybridizations and data collection on 5 paired NKG2C+ and NKG2C- IE and PB âCTL samples was preformed at the Functional Genomics Facility, University of Chicago. Briefly, 10ug of total RNA, extracted using the RNeasy Mini kit (Qiagen, Valencia, CA), was used to generate double-stranded cDNA using a T7 linked oligo dT primer and the Superscript II RT system (Invitrogen Carlsbad CA). Purified cDNA was then used to generate biotin-labeled cRNA using the BioArray High Yield RNA Transcript Labeling Kit (Enzo Diagnostics, Farmingdale, NY) according to the manufacturers protocol. This biotinylated-cRNA was then fragmented and hybridized to an Affymetrix GeneChip HG-U133. The arrays were then washed and stained with phycoerythrin-conjugated streptavidin according to the Affymetrix GeneChip protocol and scanned using the Affymetrix Agilent GeneArray Scanner (Affymetrix, Santa Clara CA). Data analyses were preformed using DNA-Chip Analyzer 1.3 (dChip) with the *.CEL files obtained from GeneChip Operating System 1.3 (GCOS 1.3). A PM-only model was used to estimate gene expression level and the invariant set approach was used for normalization. For comparison analyses of the paired NKG2C+ and NKG2C- populations, thresholds for selecting significant genes were set at a relative difference > 1.5 fold, absolute difference > 100 and a significant paired t-test for the signal intensity difference at p < 0.05. Duplicate genes and genes of unknown function were removed. The remaining genes were then grouped based on function and cluster analysis was preformed using dChip.

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A human autoimmune organoid model reveals IL-7 function in celiac disease

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