{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:10:17Z","timestamp":1785424217988,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,5]]},"group-title":"Immunology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["NIH R01 DK133393"],"award-info":[{"award-number":["NIH R01 DK133393"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["NIH R01 AI038339"],"award-info":[{"award-number":["NIH R01 AI038339"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02xhk2825","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,5]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>The liver, pancreas, and duodenum share lymph nodes (LNs), providing a unique system to examine how tissue origin of self-antigens shapes T cell fate. Comparing mice expressing ovalbumin (OVA) from distinct subcellular compartments, we found that cytosolic OVA from liver or pancreas, but not gut, was immunologically ignored. High-dose hepatic secreted OVA triggered antigen-specific T cell deletion, whereas secreted pancreatic and intestinal OVA induced regulatory T (Treg) cells, revealing immunological ignorance, clonal deletion and Treg cell generation as tissue-specific tolerance mechanisms. Of these, LN co-drainage only influenced Treg cell induction, establishing gut-pancreas-liver axes: Intestinal viral infection rendered hepatocyte- and exocrine pancreas-specific T cells inflammatory; liver injury promoted pancreas- and gut-directed responses. These self-reactive T cells caused tissue destruction but enhanced pancreatic tumor control when neoantigen OVA was secreted but not cytosolic. Thus, LN co-drainage and tissue-specific tolerance mechanisms jointly shape immune homeostasis and disease susceptibility in the upper digestive system.<\/jats:p>","DOI":"10.64898\/2025.12.02.691870","type":"posted-content","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T12:44:09Z","timestamp":1765197849000},"source":"Crossref","is-referenced-by-count":0,"title":["Tissue-specific tolerance mechanisms and lymph node co-drainage converge to shape T cell immunity in the upper digestive system and regulate pancreatic cancer progression"],"prefix":"10.64898","author":[{"given":"Yixuan D.","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Schaffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macy R.","family":"Komnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwen M.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay L.","family":"Fiske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Sheehan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence S.","family":"Dermody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Muir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Esterh\u00e1zy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120818201729000_2025.12.02.691870v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.01.042"},{"key":"2025120818201729000_2025.12.02.691870v1.2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1320"},{"key":"2025120818201729000_2025.12.02.691870v1.3","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0413207"},{"key":"2025120818201729000_2025.12.02.691870v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1125-3"},{"key":"2025120818201729000_2025.12.02.691870v1.5","doi-asserted-by":"crossref","first-page":"116441","DOI":"10.1016\/j.celrep.2025.116441","article-title":"Medullary stromal cells define small intestinal lymph node identity in humans and mice","volume":"44","year":"2025","journal-title":"Cell Rep"},{"key":"2025120818201729000_2025.12.02.691870v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.07.008"},{"key":"2025120818201729000_2025.12.02.691870v1.7","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.06.687030"},{"key":"2025120818201729000_2025.12.02.691870v1.8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02616"},{"key":"2025120818201729000_2025.12.02.691870v1.9","doi-asserted-by":"publisher","DOI":"10.1007\/s11248-019-00177-8"},{"key":"2025120818201729000_2025.12.02.691870v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/223472a0"},{"key":"2025120818201729000_2025.12.02.691870v1.11","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev-immunol-090122-041354","article-title":"Priming and Maintenance of Adaptive Immunity in the Liver","volume":"42","year":"2024","journal-title":"Annu Rev Immunol"},{"key":"2025120818201729000_2025.12.02.691870v1.12","first-page":"92","article-title":"Unlocking CD8+ T cell potential in chronic hepatitis B virus infection","volume":"22","year":"2024","journal-title":"Nature Reviews Gastroenterology & Hepatology"},{"key":"2025120818201729000_2025.12.02.691870v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah5298"},{"key":"2025120818201729000_2025.12.02.691870v1.14","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00182-13"},{"key":"2025120818201729000_2025.12.02.691870v1.15","doi-asserted-by":"crossref","first-page":"951019","DOI":"10.3389\/fonc.2022.951019","article-title":"The immunoregulation ebect of tumor microenvironment in pancreatic ductal adenocarcinoma","volume":"12","year":"2022","journal-title":"Front Oncol"},{"key":"2025120818201729000_2025.12.02.691870v1.16","doi-asserted-by":"crossref","unstructured":"Apiz Saab, J. 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