{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T14:48:45Z","timestamp":1780930125658,"version":"3.54.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institutes of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["K08DK123403"],"award-info":[{"award-number":["K08DK123403"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ulcerative colitis (UC) is a chronic gastrointestinal condition with high morbidity. Modern therapies have revolutionized the care of UC, but 10% to 25% of patients do not respond to treatments and many progress to surgery. Thus, developing new treatments remains an important goal in UC. T cells, especially T helper 17 (Th17) cells, are linked with the pathogenesis of UC and are thought to be major targets of medications in UC. Therefore, we considered cytokines that may regulate pathogenic T cells in UC, focusing on cytokines that regulate T cells in tissue, as the intestinal microenvironment contains specialized noncirculating T cell subsets. Using public sequencing datasets, we identified that the IL15 axis is upregulated in UC and CD4+ T cells that express the specificity conferring receptor for IL-15 (IL-2RB) exhibit a pathogenic Th17 signature. Using a combination of murine models and human biospecimens, we verified that pathogenic Th17 cells express IL-2RB. IL-15 was redundant for Th17 differentiation, but IL-15 could activate terminally differentiated Th17 cells in the colon in a JAK1-dependent manner. Thus, we found that the IL15 axis is upregulated in UC and that IL-15 can activate inflammatory Th17 cells in the colon, raising the possibility that IL-15 is a potential target for UC treatments.<\/jats:p>","DOI":"10.1093\/ibd\/izaf222","type":"journal-article","created":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T09:46:23Z","timestamp":1762681583000},"page":"3417-3428","source":"Crossref","is-referenced-by-count":1,"title":["IL-15 Promotes Inflammatory Th17 Cells in the Intestine"],"prefix":"10.1093","volume":"31","author":[{"given":"Guoqing","family":"Hou","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4861-7646","authenticated-orcid":false,"given":"Allen","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0009-5815","authenticated-orcid":false,"given":"Jonathan L","family":"Golob","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4065-4418","authenticated-orcid":false,"given":"Helmut","family":"Grasberger","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliott","family":"Berinstein","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreenath R","family":"Bishu","sequence":"additional","affiliation":[{"name":"Laboratory and Pathology Diagnostics, 1220 Hobson Road, Naperville, Illnois, 60540,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed El","family":"Zataari","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Khaykin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff A","family":"Berinstein","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Fry","sequence":"additional","affiliation":[{"name":"Unit of Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2392-9870","authenticated-orcid":false,"given":"Jean","family":"Nemzek","sequence":"additional","affiliation":[{"name":"Unit of Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1980-4178","authenticated-orcid":false,"given":"Nobuhiko","family":"Kamada","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kao","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-5805","authenticated-orcid":false,"given":"Shrinivas","family":"Bishu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Michigan, Ann Arbor, MI ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"2025120914524996200_izaf222-B1","doi-asserted-by":"crossref","first-page":"384","DOI":"10.14309\/ajg.0000000000000152","article-title":"ACG clinical guideline: ulcerative colitis in adults","volume":"114","author":"Rubin","year":"2019","journal-title":"Am J Gastroenterol"},{"key":"2025120914524996200_izaf222-B2","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1016\/j.cgh.2021.05.038","article-title":"Tofacitinib for biologic-experienced hospitalized patients with acute severe ulcerative colitis: a retrospective case-control study","volume":"19","author":"Berinstein","year":"2021","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2025120914524996200_izaf222-B3","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1093\/ibd\/izz316","article-title":"Th17 cells in inflammatory bowel disease: an update for the clinician","volume":"26","author":"Hou","year":"2020","journal-title":"Inflamm Bowel Dis"},{"key":"2025120914524996200_izaf222-B4","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature11582","article-title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature"},{"key":"2025120914524996200_izaf222-B5","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1053\/j.gastro.2016.09.032","article-title":"Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease","volume":"152","author":"Brant","year":"2017","journal-title":"Gastroenterology"},{"key":"2025120914524996200_izaf222-B6","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1126\/science.1135245","article-title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene","volume":"314","author":"Duerr","year":"2006","journal-title":"Science"},{"key":"2025120914524996200_izaf222-B7","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s41590-019-0415-0","article-title":"Targeting immune cell circuits and trafficking in inflammatory bowel disease","volume":"20","author":"Neurath","year":"2019","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B8","doi-asserted-by":"crossref","first-page":"7061","DOI":"10.1073\/pnas.1415675112","article-title":"Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis","volume":"112","author":"Harbour","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025120914524996200_izaf222-B9","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1136\/gutjnl-2011-301668","article-title":"Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn\u2019s disease: unexpected results of a randomised, double-blind placebo-controlled trial","volume":"61","author":"Hueber","year":"2012","journal-title":"Gut"},{"key":"2025120914524996200_izaf222-B10","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.immuni.2015.08.019","article-title":"Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation","volume":"43","author":"Maxwell","year":"2015","journal-title":"Immunity"},{"key":"2025120914524996200_izaf222-B11","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.immuni.2015.09.003","article-title":"Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability","volume":"43","author":"Lee","year":"2015","journal-title":"Immunity"},{"key":"2025120914524996200_izaf222-B12","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/ni.2416","article-title":"Induction and molecular signature of pathogenic TH17 cells","volume":"13","author":"Lee","year":"2012","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B13","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature11981","article-title":"Dynamic regulatory network controlling TH17 cell differentiation","volume":"496","author":"Yosef","year":"2013","journal-title":"Nature"},{"key":"2025120914524996200_izaf222-B14","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1016\/j.celrep.2017.08.078","article-title":"Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites","volume":"20","author":"Kumar","year":"2017","journal-title":"Cell Rep"},{"key":"2025120914524996200_izaf222-B15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.immuni.2018.01.007","article-title":"Human T cell development, localization, and function throughout life","volume":"48","author":"Kumar","year":"2018","journal-title":"Immunity"},{"key":"2025120914524996200_izaf222-B16","doi-asserted-by":"crossref","first-page":"eabb4432","DOI":"10.1126\/sciimmunol.abb4432","article-title":"Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses","volume":"5","author":"Boland","year":"2020","journal-title":"Sci Immunol"},{"key":"2025120914524996200_izaf222-B17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41590-018-0298-5","article-title":"Hobit- and Blimp-1-driven CD4(+) tissue-resident memory T cells control chronic intestinal inflammation","volume":"20","author":"Zundler","year":"2019","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B18","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.immuni.2019.03.028","article-title":"The gammac family of cytokines: basic biology to therapeutic ramifications","volume":"50","author":"Leonard","year":"2019","journal-title":"Immunity"},{"key":"2025120914524996200_izaf222-B19","doi-asserted-by":"crossref","first-page":"3608","DOI":"10.4049\/jimmunol.164.7.3608","article-title":"IL-15 is highly expressed in inflammatory bowel disease and regulates local T cell-dependent cytokine production","volume":"164","author":"Liu","year":"2000","journal-title":"J Immunol"},{"key":"2025120914524996200_izaf222-B20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/imm.12014","article-title":"Interleukin-15 receptor alpha expression in inflammatory bowel disease patients before and after normalization of inflammation with infliximab","volume":"138","author":"Perrier","year":"2013","journal-title":"Immunology"},{"key":"2025120914524996200_izaf222-B21","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1038\/ni.2449","article-title":"Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15","volume":"13","author":"Ring","year":"2012","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B22","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/ni1492","article-title":"Crystal structure of the IL-15-IL-15Ralpha complex, a cytokine-receptor unit presented in trans","volume":"8","author":"Chirifu","year":"2007","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B23","doi-asserted-by":"crossref","first-page":"10888","DOI":"10.1038\/ncomms10888","article-title":"IL-15-dependent balance between Foxp3 and RORgammat expression impacts inflammatory bowel disease","volume":"7","author":"Tosiek","year":"2016","journal-title":"Nat Commun"},{"key":"2025120914524996200_izaf222-B24","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.4049\/jimmunol.1201476","article-title":"The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes","volume":"189","author":"Pandiyan","year":"2012","journal-title":"J Immunol"},{"key":"2025120914524996200_izaf222-B25","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1053\/j.gastro.2013.06.010","article-title":"Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis","volume":"146","author":"Sandborn","year":"2014","journal-title":"Gastroenterology"},{"key":"2025120914524996200_izaf222-B26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1053\/j.gastro.2013.05.048","article-title":"Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis","volume":"146","author":"Sandborn","year":"2014","journal-title":"Gastroenterology"},{"key":"2025120914524996200_izaf222-B27","doi-asserted-by":"crossref","first-page":"18243","DOI":"10.1038\/s41598-021-97366-5","article-title":"Meta-analysis of gene expression disease signatures in colonic biopsy tissue from patients with ulcerative colitis","volume":"11","author":"Linggi","year":"2021","journal-title":"Sci Rep"},{"key":"2025120914524996200_izaf222-B28","doi-asserted-by":"crossref","first-page":"baae026","DOI":"10.1093\/database\/baae026","article-title":"IBDTransDB: a manually curated transcriptomic database for inflammatory bowel disease","volume":"2024","author":"Avram","year":"2024","journal-title":"Database (Oxford)"},{"key":"2025120914524996200_izaf222-B29","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/ecco-jcc\/jjz010","article-title":"CD4+ tissue-resident memory T cells expand and are a major source of mucosal tumour necrosis factor alpha in active Crohn\u2019s disease","volume":"13","author":"Bishu","year":"2019","journal-title":"J Crohns Colitis"},{"key":"2025120914524996200_izaf222-B30","doi-asserted-by":"crossref","first-page":"e00295","DOI":"10.1128\/IAI.00295-19","article-title":"Citrobacter rodentium induces tissue-resident memory CD4(+) T cells","volume":"87","author":"Bishu","year":"2019","journal-title":"Infect Immun"},{"key":"2025120914524996200_izaf222-B31","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.cell.2019.07.032","article-title":"Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection","volume":"178","author":"Amezcua Vesely","year":"2019","journal-title":"Cell"},{"key":"2025120914524996200_izaf222-B32","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.immuni.2019.05.004","article-title":"The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells","volume":"51","author":"Omenetti","year":"2019","journal-title":"Immunity"},{"key":"2025120914524996200_izaf222-B33","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.cell.2019.06.029","article-title":"Intra- and Inter-cellular rewiring of the human colon during ulcerative colitis","volume":"178","author":"Smillie","year":"2019","journal-title":"Cell"},{"key":"2025120914524996200_izaf222-B34","doi-asserted-by":"crossref","first-page":"eabl5197","DOI":"10.1126\/science.abl5197","article-title":"Cross-tissue immune cell analysis reveals tissue-specific features in humans","volume":"376","author":"Dominguez Conde","year":"2022","journal-title":"Science"},{"key":"2025120914524996200_izaf222-B35","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/s41590-020-0602-z","article-title":"Distinct microbial and immune niches of the human colon","volume":"21","author":"James","year":"2020","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B36","doi-asserted-by":"crossref","first-page":"eaaw2262","DOI":"10.1126\/sciimmunol.aaw2262","article-title":"T(H)17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity","volume":"5","author":"Harbour","year":"2020","journal-title":"Sci Immunol"},{"key":"2025120914524996200_izaf222-B37","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/nature09447","article-title":"Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling","volume":"467","author":"Ghoreschi","year":"2010","journal-title":"Nature"},{"key":"2025120914524996200_izaf222-B38","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1016\/j.celrep.2018.02.044","article-title":"IL-23 and IL-1beta drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation","volume":"22","author":"Revu","year":"2018","journal-title":"Cell Rep"},{"key":"2025120914524996200_izaf222-B39","doi-asserted-by":"crossref","first-page":"e20191761","DOI":"10.1084\/jem.20191761","article-title":"Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen","volume":"217","author":"Poholek","year":"2020","journal-title":"J Exp Med"},{"key":"2025120914524996200_izaf222-B40","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1084\/jem.20080218","article-title":"Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3","volume":"205","author":"Ma","year":"2008","journal-title":"J Exp Med"},{"key":"2025120914524996200_izaf222-B41","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.immuni.2020.12.010","article-title":"The TGF-beta superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation","volume":"54","author":"Wu","year":"2021","journal-title":"Immunity"},{"key":"2025120914524996200_izaf222-B42","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nature14452","article-title":"Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation","volume":"523","author":"Gagliani","year":"2015","journal-title":"Nature"},{"key":"2025120914524996200_izaf222-B43","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nri3919","article-title":"IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction","volume":"15","author":"Jabri","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"2025120914524996200_izaf222-B44","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1038\/ni.3540","article-title":"An essential role for the IL-2 receptor in Treg cell function","volume":"17","author":"Chinen","year":"2016","journal-title":"Nat Immunol"},{"key":"2025120914524996200_izaf222-B45","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.4049\/jimmunol.164.5.2832","article-title":"High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism","volume":"164","author":"Ziolkowska","year":"2000","journal-title":"J Immunol"},{"key":"2025120914524996200_izaf222-B46","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/nri3707","article-title":"The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing","volume":"14","author":"Gaffen","year":"2014","journal-title":"Nat Rev Immunol"}],"container-title":["Inflammatory Bowel Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ibdjournal\/article-pdf\/31\/12\/3417\/65242044\/izaf222.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ibdjournal\/article-pdf\/31\/12\/3417\/65242044\/izaf222.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T19:53:02Z","timestamp":1765309982000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ibdjournal\/article\/31\/12\/3417\/8316929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,11,5]]},"published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ibd\/izaf222","relation":{},"ISSN":["1078-0998","1536-4844"],"issn-type":[{"value":"1078-0998","type":"print"},{"value":"1536-4844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,11,5]]}}}