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T-cell receptor (TCR) repertoires directed to some immunodominant gluten peptides have previously been described, but the global immune response to <jats:italic>in vivo<\/jats:italic> gluten exposure in CD has not been systematically investigated yet. Here, we characterized signatures associated with gluten directed immune activity and identified gluten-induced T-cell clonotypes from total blood and gut TCR repertoires in an unbiased manner using immunosequencing. CD patient total TCR repertoires showed increased overlap and substantially altered TRBV-gene usage in both blood and gut samples, and increased diversity in the gut during gluten exposure. Using differential abundance analysis, we identified gluten-induced clonotypes in each patient that were composed of a large private and an important public component. Hierarchical clustering of public clonotypes associated with dietary gluten exposure identified subsets of highly similar clonotypes, the most proliferative of which showing significant enrichment for the motif ASS[LF]R[SW][TD][DT][TE][QA][YF] in PBMC repertoires. These results show that CD-associated clonotypes can be identified and that common gluten associated immune response features can be characterized <jats:italic>in vivo<\/jats:italic> from total repertoires, with potential use in disease stratification and monitoring.<\/jats:p>","DOI":"10.1038\/s41598-017-18137-9","type":"journal-article","created":{"date-parts":[[2017,12,15]],"date-time":"2017-12-15T11:32:42Z","timestamp":1513337562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Deep sequencing of blood and gut T-cell receptor \u03b2-chains reveals gluten-induced immune signatures in celiac disease"],"prefix":"10.1038","volume":"7","author":[{"given":"Dawit A.","family":"Yohannes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias L.","family":"Freitag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"de Kauwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katri","family":"Kaukinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalle","family":"Kurppa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pirjo","family":"Wacklin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"M\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Petteri","family":"Arstila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"Saavalainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,21]]},"reference":[{"key":"18137_CR1","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3109\/07853890.2010.505931","volume":"42","author":"K Mustalahti","year":"2010","unstructured":"Mustalahti, K. et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann. Med. \n                           42, 587\u2013595 (2010).","journal-title":"Ann. 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In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat. Med. \n                           6, 337\u2013342 (2000).","journal-title":"Nat. Med."},{"key":"18137_CR5","doi-asserted-by":"publisher","first-page":"41ra51","DOI":"10.1126\/scitranslmed.3001012","volume":"2","author":"JA Tye-Din","year":"2010","unstructured":"Tye-Din, J. A. et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl. Med. \n                           2, 41ra51 (2010).","journal-title":"Sci. Transl. Med."},{"key":"18137_CR6","doi-asserted-by":"publisher","unstructured":"Cook, L. et al. Circulating Gluten-Specific FOXP3(+)CD39(+) Regulatory T Cells Have Impaired Suppressive Function in Celiac Disease. J. Allergy Clin. 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RPA is also an employee and shareholder of ImmusanT Inc (a company developing therapeutics and diagnostics for coeliac disease), and is also a shareholder in Nexpep Pty. Ltd, which holds shares in ImmusanT, Inc. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"17977"}}