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

António J. M. Santos, Vincent Unen, Zhongqi Lin, Steven M. Chirieleison, Nhi Ha, Arpit Batish, Joshua E. Chan, Jose Cedano, Elisa T. Zhang, Qinghui Mu, Alexander Guh-Siesel, Madeline Tomaske, Deana Colburg, Sushama Varma, Shannon S. Choi, Asbjørn Christophersen, Ani Baghdasaryan, Kathryn E. Yost, Kasper Karlsson, Andrew Ha, Jing Li, Hongjie Dai, Zachary M. Sellers, Howard Y. Chang, James C. Y. Dunn, Bing M. Zhang, Elizabeth D. Mellins, Ludvig M. Sollid, Nielsen Q. Fernandez-Becker, Mark M. Davis and Calvin J. Kuo ()
Additional contact information
António J. M. Santos: Stanford University School of Medicine
Vincent Unen: Stanford University School of Medicine
Zhongqi Lin: Stanford University School of Medicine
Steven M. Chirieleison: Stanford University School of Medicine
Nhi Ha: Stanford University School of Medicine
Arpit Batish: Stanford University School of Medicine
Joshua E. Chan: Stanford University School of Medicine
Jose Cedano: Stanford University School of Medicine
Elisa T. Zhang: Stanford University School of Medicine
Qinghui Mu: Stanford University School of Medicine
Alexander Guh-Siesel: Stanford University School of Medicine
Madeline Tomaske: Stanford University School of Medicine
Deana Colburg: Stanford University School of Medicine
Sushama Varma: Stanford University School of Medicine
Shannon S. Choi: Stanford University School of Medicine
Asbjørn Christophersen: University of Oslo
Ani Baghdasaryan: Stanford University School of Medicine
Kathryn E. Yost: Stanford University School of Medicine
Kasper Karlsson: Stanford University School of Medicine
Andrew Ha: Stanford University School of Medicine
Jing Li: Stanford University School of Medicine
Hongjie Dai: Stanford University School of Medicine
Zachary M. Sellers: Stanford University School of Medicine
Howard Y. Chang: Stanford University School of Medicine
James C. Y. Dunn: Stanford University School of Medicine
Bing M. Zhang: Stanford University School of Medicine
Elizabeth D. Mellins: Stanford University School of Medicine
Ludvig M. Sollid: University of Oslo
Nielsen Q. Fernandez-Becker: Stanford University School of Medicine
Mark M. Davis: Stanford University School of Medicine
Calvin J. Kuo: Stanford University School of Medicine

Nature, 2024, vol. 632, issue 8024, 401-410

Abstract: Abstract 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 injury1–4. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07716-2

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