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We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.<\/jats:p>","DOI":"10.1182\/blood.2019004116","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T21:17:53Z","timestamp":1585689473000},"page":"2388-2401","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":64,"title":["An intestinal organoid\u2013based platform that recreates susceptibility to T-cell\u2013mediated tissue injury"],"prefix":"10.1182","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5675-6793","authenticated-orcid":false,"given":"Yu","family":"Matsuzawa-Ishimoto","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"},{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Hine","sequence":"first","affiliation":[{"name":"Department of Microbiology, and"},{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0459-1659","authenticated-orcid":false,"given":"Yusuke","family":"Shono","sequence":"first","affiliation":[{"name":"Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Rudensky","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"},{"name":"Sackler Institute of Graduate Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amina","family":"Lazrak","sequence":"first","affiliation":[{"name":"Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Yeung","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"},{"name":"Sackler Institute of Graduate Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Neil","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"},{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4045-8836","authenticated-orcid":false,"given":"Xiaomin","family":"Yao","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"},{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Han","family":"Chen","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"},{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4909-6851","authenticated-orcid":false,"given":"Thomas","family":"Heaney","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha L.","family":"Schuster","sequence":"first","affiliation":[{"name":"Kimmel Center for Biology and Medicine at the Skirball Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin E.","family":"Zwack","sequence":"first","affiliation":[{"name":"Department of Microbiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1951-7790","authenticated-orcid":false,"given":"Jordan E.","family":"Axelrad","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hudesman","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0817-1667","authenticated-orcid":false,"given":"Katherine","family":"Nichols","sequence":"first","affiliation":[{"name":"Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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