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

• 成果类型: Article
• 署名作者: Santos, Antonio J. M.; van Unen, Vincent; Lin, Zhongqi; Chirieleison, Steven M.; Ha, Nhi; Batish, Arpit; Chan, Joshua E.; Cedano, Jose; Zhang, Elisa T.; Mu, Qinghui; Guh-Siesel, Alexander; Tomaske, Madeline; Colburg, Deana; Varma, Sushama; Choi, Shannon S.; Christophersen, Asbjorn; Baghdasaryan, Ani; Yost, Kathryn E.; Karlsson, Kasper; Ha, Andrew; Li, Jing; Dai, Hongjie; Sellers, Zachary M.; Chang, Howard Y.; Dunn, James C. Y.; Zhang, Bing M.; Mellins, Elizabeth D.; Sollid, Ludvig M.; Fernandez-Becker, Nielsen Q.; Davis, Mark M.; Kuo, Calvin J.
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford University; University of Oslo; University of Oslo; University of Oslo; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4933
• DOI: 10.1038/s41586-024-07716-2
• 发表日期: 2024-08-08
• 页码: 401-+
• 关键词: major histocompatibility complex; t-cells; small-intestine; class-ii; interleukin-7; gliadin; mice; peptide; gluten; roles

摘要

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury(1-4). Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8(+) T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.