{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:23:09Z","timestamp":1792621389705,"version":"4.5.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"7796","license":[{"start":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2020,2,27]]},"DOI":"10.1038\/s41586-020-2003-8","type":"journal-article","created":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T14:02:33Z","timestamp":1581516153000},"page":"600-604","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":231,"title":["IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease"],"prefix":"10.1038","volume":"578","author":[{"given":"Vale\u0301rie","family":"Abadie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangman M.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lejeune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad A.","family":"Palanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D.","family":"Ernest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Tastet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Voisine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Discepolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric V.","family":"Marietta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed B. F.","family":"Hawash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezary","family":"Ciszewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Bouziat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaushik","family":"Panigrahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Horwath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Zurenski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Lawrence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Dumaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania","family":"Yotova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Christophe","family":"Grenier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaitan","family":"Khosla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis B.","family":"Barreiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bana","family":"Jabri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,12]]},"reference":[{"key":"2003_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1146\/annurev-immunol-040210-092915","volume":"29","author":"V Abadie","year":"2011","unstructured":"Abadie, V., Sollid, L. M., Barreiro, L. B. & Jabri, B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu. Rev. Immunol. 29, 493\u2013525 (2011).","journal-title":"Annu. Rev. Immunol."},{"key":"2003_CR2","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1056\/NEJMra071600","volume":"357","author":"PH Green","year":"2007","unstructured":"Green, P. H. & Cellier, C. Celiac disease. N. Engl. J. Med. 357, 1731\u20131743 (2007).","journal-title":"N. Engl. J. Med."},{"key":"2003_CR3","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.bpg.2015.04.005","volume":"29","author":"NM Plugis","year":"2015","unstructured":"Plugis, N. M. & Khosla, C. Therapeutic approaches for celiac disease. Best Pract. Res. Clin. Gastroenterol. 29, 503\u2013521 (2015).","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"2003_CR4","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/nri2670","volume":"9","author":"B Jabri","year":"2009","unstructured":"Jabri, B. & Sollid, L. M. Tissue-mediated control of immunopathology in coeliac disease. Nat. Rev. Immunol. 9, 858\u2013870 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"2003_CR5","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1097\/MPG.0b013e31821a23d0","volume":"54","author":"S Husby","year":"2012","unstructured":"Husby, S. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 54, 136\u2013160 (2012).","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"2003_CR6","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/nm0797-797","volume":"3","author":"W Dieterich","year":"1997","unstructured":"Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797\u2013801 (1997).","journal-title":"Nat. Med."},{"key":"2003_CR7","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nri3919","volume":"15","author":"B Jabri","year":"2015","unstructured":"Jabri, B. & Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat. Rev. Immunol. 15, 771\u2013783 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"2003_CR8","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/nri1901","volume":"6","author":"TA Waldmann","year":"2006","unstructured":"Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6, 595\u2013601 (2006).","journal-title":"Nat. Rev. Immunol."},{"key":"2003_CR9","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1053\/j.gastro.2015.05.013","volume":"149","author":"M Setty","year":"2015","unstructured":"Setty, M. et al. Distinct and synergistic contributions of epithelial stress and adaptive immunity to functions of intraepithelial killer cells and active celiac disease. Gastroenterol. 149, 681\u2013691 (2015).","journal-title":"Gastroenterol."},{"key":"2003_CR10","doi-asserted-by":"publisher","first-page":"5595","DOI":"10.4049\/jimmunol.169.10.5595","volume":"169","author":"KE Black","year":"2002","unstructured":"Black, K. E., Murray, J. A. & David, C. S. HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J. Immunol. 169, 5595\u20135600 (2002).","journal-title":"J. Immunol."},{"key":"2003_CR11","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/ncpgasthep0582","volume":"3","author":"B Jabri","year":"2006","unstructured":"Jabri, B. & Sollid, L. M. Mechanisms of disease: immunopathogenesis of celiac disease. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 516\u2013525 (2006).","journal-title":"Nat. Clin. Pract. Gastroenterol. Hepatol."},{"key":"2003_CR12","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1053\/j.gastro.2013.12.023","volume":"146","author":"N Korneychuk","year":"2014","unstructured":"Korneychuk, N. et al. Interleukin 15 and CD4+ T cells cooperate to promote small intestinal enteropathy in response to dietary antigen. Gastroenterology 146, 1017\u20131027 (2014).","journal-title":"Gastroenterology"},{"key":"2003_CR13","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/nature09849","volume":"471","author":"RW DePaolo","year":"2011","unstructured":"DePaolo, R. W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220\u2013224 (2011).","journal-title":"Nature"},{"key":"2003_CR14","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/nm.2656","volume":"18","author":"R Di Niro","year":"2012","unstructured":"Di Niro, R. et al. High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat. Med. 18, 441\u2013445 (2012).","journal-title":"Nat. Med."},{"key":"2003_CR15","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/S0016-5085(98)70134-9","volume":"115","author":"EM Nilsen","year":"1998","unstructured":"Nilsen, E. M. et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 115, 551\u2013563 (1998).","journal-title":"Gastroenterology"},{"key":"2003_CR16","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1084\/jem.20060028","volume":"203","author":"B Meresse","year":"2006","unstructured":"Meresse, B. et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J. Exp. Med. 203, 1343\u20131355 (2006).","journal-title":"J. Exp. Med."},{"key":"2003_CR17","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.immuni.2004.06.020","volume":"21","author":"B Meresse","year":"2004","unstructured":"Meresse, B. et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357\u2013366 (2004).","journal-title":"Immunity"},{"key":"2003_CR18","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.immuni.2004.06.018","volume":"21","author":"S H\u00fce","year":"2004","unstructured":"H\u00fce, S. et al. A direct role for NKG2D\/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367\u2013377 (2004).","journal-title":"Immunity"},{"key":"2003_CR19","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/mi.2010.36","volume":"3","author":"M Bodd","year":"2010","unstructured":"Bodd, M. et al. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol. 3, 594\u2013601 (2010).","journal-title":"Mucosal Immunol."},{"key":"2003_CR20","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.4049\/jimmunol.161.4.1585","volume":"161","author":"Y van de Wal","year":"1998","unstructured":"van de Wal, Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J. Immunol. 161, 1585\u20131588 (1998).","journal-title":"J. Immunol."},{"key":"2003_CR21","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/nm0698-713","volume":"4","author":"O Molberg","year":"1998","unstructured":"Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713\u2013717 (1998).","journal-title":"Nat. Med."},{"key":"2003_CR22","doi-asserted-by":"publisher","first-page":"9042","DOI":"10.1021\/jm501145a","volume":"57","author":"C Kl\u00f6ck","year":"2014","unstructured":"Kl\u00f6ck, C., Herrera, Z., Albertelli, M. & Khosla, C. Discovery of potent and specific dihydroisoxazole inhibitors of human transglutaminase 2. J. Med. Chem. 57, 9042\u20139064 (2014).","journal-title":"J. Med. Chem."},{"key":"2003_CR23","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1136\/gut.2009.186361","volume":"58","author":"TL Freitag","year":"2009","unstructured":"Freitag, T. L. et al. Gliadin-primed CD4+CD45RBlowCD25\u2212 T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice. Gut 58, 1597\u20131605 (2009).","journal-title":"Gut"},{"key":"2003_CR24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/ismej.2016.114","volume":"11","author":"M Meisel","year":"2017","unstructured":"Meisel, M. et al. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. ISME J. 11, 15\u201330 (2017).","journal-title":"ISME J."},{"key":"2003_CR25","doi-asserted-by":"publisher","first-page":"6476","DOI":"10.1074\/jbc.274.10.6476","volume":"274","author":"D Pinto","year":"1999","unstructured":"Pinto, D., Robine, S., Jaisser, F., El Marjou, F. E. & Louvard, D. Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines. J. Biol. Chem. 274, 6476\u20136482 (1999).","journal-title":"J. Biol. Chem."},{"key":"2003_CR26","first-page":"Unit 3.19","volume":"Chapter 3","author":"L Lefrancois","year":"2001","unstructured":"Lefrancois, L. & Lycke, N. Isolation of mouse small intestinal intraepithelial lymphocytes, Peyer's patch, and lamina propria cells. Curr. Protoc. Immunol. Chapter 3, Unit 3.19 (2001).","journal-title":"Curr. Protoc. Immunol."},{"key":"2003_CR27","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1126\/science.aah5298","volume":"356","author":"R Bouziat","year":"2017","unstructured":"Bouziat, R. et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356, 44\u201350 (2017).","journal-title":"Science"},{"key":"2003_CR28","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1021\/cb4006408","volume":"9","author":"TR DiRaimondo","year":"2014","unstructured":"DiRaimondo, T. R. et al. Elevated transglutaminase 2 activity is associated with hypoxia-induced experimental pulmonary hypertension in mice. ACS Chem. Biol. 9, 266\u2013275 (2014).","journal-title":"ACS Chem. Biol."},{"key":"2003_CR29","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1093\/bioinformatics\/btn224","volume":"24","author":"P Du","year":"2008","unstructured":"Du, P., Kibbe, W. A. & Lin, S. M. lumi: a pipeline for processing Illumina microarray. Bioinformatics 24, 1547\u20131548 (2008).","journal-title":"Bioinformatics"},{"key":"2003_CR30","doi-asserted-by":"publisher","first-page":"e11","DOI":"10.1093\/nar\/gkm1075","volume":"36","author":"SM Lin","year":"2008","unstructured":"Lin, S. M., Du, P., Huber, W. & Kibbe, W. A. Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res. 36, e11 (2008).","journal-title":"Nucleic Acids Res."},{"key":"2003_CR31","doi-asserted-by":"publisher","first-page":"Article3","DOI":"10.2202\/1544-6115.1027","volume":"3","author":"GK Smyth","year":"2004","unstructured":"Smyth, G. K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3, Article3 (2004).","journal-title":"Stat Appl Genet Mol Biol"},{"key":"2003_CR32","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"YHY Benjamini","year":"1995","unstructured":"Benjamini, Y. H. Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. A Stat. Soc. 57, 289\u2013300 (1995).","journal-title":"J. R. Stat. Soc. Ser. A Stat. Soc."},{"key":"2003_CR33","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","volume":"34","author":"NL Bray","year":"2016","unstructured":"Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525\u2013527 (2016).","journal-title":"Nat. Biotechnol."},{"key":"2003_CR34","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2010).","journal-title":"Bioinformatics"},{"key":"2003_CR35","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).","journal-title":"Nucleic Acids Res."},{"key":"2003_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-48","volume":"10","author":"E Eden","year":"2009","unstructured":"Eden, E., Navon, R., Steinfeld, I., Lipson, D. & Yakhini, Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10, 48 (2009).","journal-title":"BMC Bioinformatics"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41586-020-2003-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41586-020-2003-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41586-020-2003-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T10:32:29Z","timestamp":1722421949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-020-2003-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,12]]},"references-count":36,"journal-issue":{"issue":"7796","published-print":{"date-parts":[[2020,2,27]]}},"alternative-id":["2003"],"URL":"https:\/\/doi.org\/10.1038\/s41586-020-2003-8","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,12]]},"assertion":[{"value":"30 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"B.J. and J.A.M. are consultants to Celimmune and Bionix. C.K. is a member of the Board of Directors of Protagonist Therapeutics. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}