{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:05:03Z","timestamp":1790085903086,"version":"4.0.1"},"reference-count":31,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014566","name":"Fondazione Celiachia","doi-asserted-by":"crossref","award":["2017_014"],"award-info":[{"award-number":["2017_014"]}],"id":[{"id":"10.13039\/501100014566","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>\u03b3\u03b4+ intraepithelial lymphocytes (IELs) are persistently expanded in the intestinal epithelium of patients with active celiac disease (ACeD), but their functional profile during active inflammation remains poorly defined. This study investigated the expression of pro- and anti-inflammatory cytokines in \u03b3\u03b4+ IELs isolated from the intestinal epithelium of ACeD patients at different stages of mucosal damage. Frozen jejunum sections were obtained from 14 ACeD patients (7 Marsh II and 7 Marsh III) and 10 treated celiac disease (CeD) patients. \u03b3\u03b4+ IELs from ACeD biopsies and intestinal enterocytes (IEs) from treated CeD biopsies were isolated by laser capture microdissection on mirror sections, followed by RNA extraction and quantitative real-time RT-PCR analysis of IL-15, IL-17A, IL-21, IFN-\u03b3, TNF-\u03b1, IL-10, and TGF-\u03b2. Foxp3 expression was assessed by immunohistochemistry. \u03b3\u03b4+ IELs from Marsh III biopsies showed significantly increased mRNA levels of IL-15, IL-17A, IL-21, IFN-\u03b3, and TGF-\u03b2 compared with IEs, whereas IL-10 expression was significantly higher in Marsh II \u03b3\u03b4+ IELs compared with Marsh III and IEs. IL-21 and TGF-\u03b2 were also higher in Marsh III than Marsh II \u03b3\u03b4+ IELs. All \u03b3\u03b4+ IELs were Foxp3\u2212. These findings indicate a stage-dependent functional polarization of \u03b3\u03b4+ IELs in ACeD, with an IL-10\u2013associated regulatory profile in Marsh II and a predominant pro-inflammatory cytokine signature in Marsh III.<\/jats:p>","DOI":"10.3390\/cells15151424","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:43:02Z","timestamp":1786016582000},"page":"1424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Celiac Disease: Cytokine Profile of Intraepithelial Gamma Delta T Cells in Disease Severity"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-8277","authenticated-orcid":false,"given":"Giuseppe","family":"Mazzarella","sequence":"first","affiliation":[{"name":"Immuno-Morphology Laboratory, Institute of Food Sciences, National Council Research, 83100 Avellino, Italy"},{"name":"European Laboratory for the Investigation of Food-Induced Diseases (E.L.F.I.D), University \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5231-2231","authenticated-orcid":false,"given":"Giuseppe","family":"Iacomino","sequence":"additional","affiliation":[{"name":"Immuno-Morphology Laboratory, Institute of Food Sciences, National Council Research, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Iaquinto","sequence":"additional","affiliation":[{"name":"Gastroenterology Division, S. Rita Hospital, 83042 Atripalda, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Camarca","sequence":"additional","affiliation":[{"name":"Immuno-Morphology Laboratory, Institute of Food Sciences, National Council Research, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Errico","family":"Picariello","sequence":"additional","affiliation":[{"name":"Immuno-Morphology Laboratory, Institute of Food Sciences, National Council Research, 83100 Avellino, Italy"},{"name":"Department of Science and Technology, University of Sannio, 82100 Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Melina","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, S. G. Moscati Hospital, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Rotondi Aufiero","sequence":"additional","affiliation":[{"name":"Immuno-Morphology Laboratory, Institute of Food Sciences, National Council Research, 83100 Avellino, Italy"},{"name":"European Laboratory for the Investigation of Food-Induced Diseases (E.L.F.I.D), University \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/nri3407","article-title":"Trained immunity and celiac disease pathogenesis","volume":"13","author":"Sollid","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/0016-5085(92)91819-P","article-title":"Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (\u201cceliac sprue\u201d)","volume":"102","author":"Marsh","year":"1992","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1097\/00042737-199910000-00019","article-title":"The histopathology of coeliac disease: Time for a standardized report scheme for pathologists","volume":"11","author":"Oberhuber","year":"1999","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1136\/jcp.2004.023978","article-title":"Coeliac disease: Some considerations on the histological diagnosis","volume":"58","author":"Corazza","year":"2005","journal-title":"J. Clin. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1159\/000260087","article-title":"Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease","volume":"152","author":"Casolaro","year":"2010","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/08916930802350789","article-title":"TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin","volume":"42","author":"Santin","year":"2009","journal-title":"Autoimmunity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.4049\/jimmunol.0901919","article-title":"Characterization of IL-17A-producing cells in celiac disease mucosa","volume":"184","author":"Monteleone","year":"2010","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/j.1365-2249.2011.04510.x","article-title":"Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes","volume":"167","author":"Ruohtula","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/ajg.2010.465","article-title":"Characterization of gliadin-specific Th17 cells from the mucosa of celiac disease patients","volume":"106","author":"Fernandez","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1038\/ajg.2011.80","article-title":"IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in celiac disease","volume":"106","author":"Zanzi","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.4049\/jimmunol.177.6.4178","article-title":"Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells","volume":"177","author":"Gianfrani","year":"2006","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7634","DOI":"10.4049\/jimmunol.177.11.7634","article-title":"Oral tolerance induction with antigen conjugated to cholera toxin B subunit generates both Foxp3+ CD25+ and Foxp3\u2212 CD25\u2212 CD4+ regulatory T cells","volume":"177","author":"Sun","year":"2006","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.smim.2011.07.008","article-title":"Clinical perspectives for regulatory T cells in transplantation tolerance","volume":"23","author":"Hippen","year":"2011","journal-title":"Semin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.intimp.2015.03.037","article-title":"The role of chemokines in adjusting the balance between CD4+ effector T cell subsets and FOXp3-negative regulatory T cells","volume":"28","author":"Karin","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/j.1365-2567.2009.03162.x","article-title":"Human peripheral gammadelta T cells possess regulatory potential","volume":"128","author":"Pawlowski","year":"2009","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1002\/eji.201948098","article-title":"The intestinal expansion of TCR\u03b3\u03b4+ and disappearance of IL4+ T cells suggest their involvement in the evolution from potential to overt celiac disease","volume":"49","author":"Vitale","year":"2019","journal-title":"Eur. J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1365-2249.1991.tb05690.x","article-title":"Gamma\/delta T cells and the diagnosis of coeliac disease","volume":"85","author":"Spencer","year":"1991","journal-title":"Clin. Exp. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1046\/j.1365-2249.1999.00948.x","article-title":"Changing jejunal gamma delta T cell receptor (TCR)-bearing intraepithelial lymphocyte density in coeliac disease","volume":"117","author":"Iltanen","year":"1999","journal-title":"Clin. Exp. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1385\/IR:21:2-3:123","article-title":"Function of intestinal gammadelta T cells","volume":"21","author":"Boismenu","year":"2000","journal-title":"Immunol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1172\/JCI30989","article-title":"Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease","volume":"118","author":"Bhagat","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113276","DOI":"10.1016\/j.jim.2022.113276","article-title":"Cell-type-specific gene expression profile by laser capture microdissection on mirror sections","volume":"505","author":"Mazzarella","year":"2022","journal-title":"J. Immunol. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Maglio, M., Ziberna, F., Aitoro, R., Discepolo, V., Lania, G., Bassi, V., Miele, E., Not, T., Troncone, R., and Auricchio, R. (2017). Intestinal production of anti-tissue transglutaminase 2 antibodies in patients with diagnosis other than celiac disease. Nutrients, 9.","DOI":"10.3390\/nu9101050"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s11010-015-2596-7","article-title":"Celiac disease: Role of intestinal compartments in the mucosal immune response","volume":"411","author":"Iacomino","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1159\/000369521","article-title":"Interleukin-15, a master piece in the immunological jigsaw of celiac disease","volume":"33","author":"Meresse","year":"2015","journal-title":"Dig. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/imr.12191","article-title":"IL-15: A central regulator of celiac disease immunopathology","volume":"260","author":"Abadie","year":"2014","journal-title":"Immunol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7349","DOI":"10.3748\/wjg.v21.i24.7349","article-title":"Effector and suppressor T cells in celiac disease","volume":"21","author":"Mazzarella","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/mi.2010.36","article-title":"HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22","volume":"3","author":"Bodd","year":"2010","journal-title":"Mucosal Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eadf4312","DOI":"10.1126\/sciimmunol.adf4312","article-title":"Gluten induces rapid reprogramming of natural memory \u03b1\u03b2 and \u03b3\u03b4 intraepithelial T cells to induce cytotoxicity in celiac disease","volume":"8","author":"Kornberg","year":"2023","journal-title":"Sci. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/s41590-025-02146-2","article-title":"Immune\u2013epithelial\u2013stromal networks define the cellular ecosystem of the small intestine in celiac disease","volume":"26","author":"FitzPatrick","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/nri1826","article-title":"De novo generation of IL-17-producing T cells","volume":"6","author":"Leavy","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1038\/ni1539","article-title":"TGF-\u03b2 and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell\u2013mediated pathology","volume":"8","author":"McGeachy","year":"2007","journal-title":"Nat. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1424\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T04:26:07Z","timestamp":1786163167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1424"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":31,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15151424"],"URL":"https:\/\/doi.org\/10.3390\/cells15151424","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]}}}