A human autoimmune organoid model reveals IL-7 function in celiac disease
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ABSTRACT:
PROVIDER: PRJNA830541 | ENA |
REPOSITORIES: ENA
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Project description: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.
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2022-12-02 | PXD036366 | Pride
Project description:Celiac disease (CeD) is an intestinal immune-mediated disorder caused by gluten ingestion in genetically predisposed subjects. CeD is characterized by villous atrophy, altered intestinal permeability, crypt hyperplasia and innate and adaptive immune response. This study aimed to develop and validate the use of intestinal organoids from celiac patients to study CeD. A repository of organoids from duodenum of non-celiac and celiac patients was generated and characterized accordingly to standard procedures. RNA-seq analysis was employed to study the global gene expression program of CeD (n=3) and non-CeD (n=3) organoids sets. While the three celiac derived organoids shared similar transcriptional signatures the NC samples set appeared more heterogeneous. We found 486 genes differentially expressed between the two groups. Of them, 299 genes were downregulated (FC<2; FDR<0.05) and 187 were upregulated in CeD (FC >2; FDR<0.05). We observed CeD organoids had significantly altered expression of genes associated with barrier function, innate immunity, and stem cell function.
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Project description:We collected 19 duodenal biopsies of children and adults with celiac disease and compared the expression of 38 selected genes between each other and with the observed in 13 non-celiac disease controls matched by age. qPCR gene expression profiling. Intestinal samples from children and adults with active celiac disease patients and controls were analysed.
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Project description:The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of pro-inflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. Here, we examined cell-type requirements and found that in addition to T cells, STAT4 is required in dendritic cells for development of EAE. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the CNS. EAE susceptibility was recovered following adoptive transfer of wild type bone marrow-derived DC to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single cell RNA-seq identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define a novel IL-23/DC/STAT4 pathway in DCs that could be a key to novel therapeutic targets in MS.
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Project description:The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.
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Project description:The nature of gut intraepithelial lymphocytes lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal intraepithelial lymphocytes expressing intracellular CD3 (iCD3+ innate IELs) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin 15 (IL-15) and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes indispensable for T cell differentiation were silenced and precursors were reprogrammed into innate cells with T cell marks including intracellular CD3 and T cell rearrangements. This pathway was operational in vivo in the mouse gut and led to the local differentiation of iCD3+ innate IELs from a bone marrow-derived precursor. In a subset of celiac patients, iCD3+ innate IELs with gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3 displayed enhanced response to IL-15 and acquired a selective advantage that favored clonal expansion and transformation into lymphoma. Overall we characterized gut T cell-like innate IELs, deciphered their pathway of differentiation, and showed their malignant transformation in celiac disease.
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