{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:13:57Z","timestamp":1792782837314,"version":"4.5.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"H.N. & Frances Berger Foundation Fellowship"},{"name":"Dr. Norman and Melinda Payson Graduate Student Fellowship"},{"name":"Anonymous donor S.S."},{"name":"The Margie & Robert E. Pertersen Foundation","id":[{"id":"https:\/\/ror.org\/04mvz4f37","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA33572"],"award-info":[{"award-number":["P30CA33572"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK099734"],"award-info":[{"award-number":["R01DK099734"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK134652"],"award-info":[{"award-number":["R01DK134652"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U24DK104162"],"award-info":[{"award-number":["U24DK104162"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"publisher","award":["EDU4-12772"],"award-info":[{"award-number":["EDU4-12772"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wanek Family Project for Type 1 Diabetes"},{"DOI":"10.13039\/100017804","name":"City of Hope","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017804","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>Type 1 diabetes is an autoimmune disease marked by the destruction of beta cells in pancreatic islets, with an incomplete picture of disease progression and a lack of a definitive cure. A recent finding linked pancreatic ductal cells of type 1 diabetic donors with elevated levels of human leukocyte antigen (HLA) class II molecules; however, the causal relationship and functional significance of this finding remain unknown. Because HLA class II molecules are typically expressed by professional antigen-presenting cells (APCs), this raises the possibility of ductal cells functioning as non-professional APCs. In this study, we test the hypothesis that ductal cells are responsive to type 1 diabetes-associated proinflammatory cytokines, TNF-\u03b1, IL-1\u03b2 and IFN-\u03b3, and can act as non-professional APCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Pancreatic exocrine cells were obtained from cadaveric donors without diabetes following islet removal. Cells were cryopreserved and thawed into a defined culture medium tailored to support ductal cell survival in a 3D suspension culture system. Ductal cells were exposed to various doses of cytokines for 48 h and analysed for gene and protein expression, using quantitative PCR with reverse transcription, bulk RNA-seq, flow cytometry and western blot analyses. Correlation between cytokine response and APC-related gene expression was evaluated using publicly available single-cell RNA-seq datasets from 86 donors. The functional ability of cytokine-treated ductal cells to present an exogenous autoantigen (glutamic acid decarboxylase 65 kDa isoform [GAD65]) to T cells was tested using a GAD65-specific autoreactive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell clone (BRI-4.13) isolated from a type 1 diabetic donor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Within 48 h, a combination of TNF-\u03b1, IL-1\u03b2 and IFN-\u03b3 stimulated mRNA and protein expression of HLA class II, co-stimulatory and antigen-processing molecules in non-diabetic ductal cells. Bulk RNA-seq analysis showed that cytokines significantly upregulated biological pathways in \u2018antigen processing and presentation\u2019 and \u2018type 1 diabetes\u2019. Single-cell RNA-seq analysis revealed a positive correlation between cytokine response and APC gene expression in human pancreatic ductal cells. Cytokine-treated ductal cells pulsed with exogenous GAD65 peptide activated and induced proliferation of BRI-4.13 T cells. Unexpectedly, ~0.9% of KRT19\n                      <jats:sup>+<\/jats:sup>\n                      ductal cells expressed GAD protein endogenously, and 26.6% of KRT19\n                      <jats:sup>+<\/jats:sup>\n                      GAD\n                      <jats:sup>+<\/jats:sup>\n                      ductal cells expressed the endocrine marker CHGA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      These results demonstrate that non-diseased primary ductal cells respond to TNF-\u03b1, IL-1\u03b2 and IFN-\u03b3 by upregulating APC molecules and presenting antigen to autoreactive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. To the best of our knowledge, our results provide the first evidence that non-diabetic human ductal cells can present antigen to T cells, which implicates ductal cells in contributing to type 1 diabetes progression.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06746-x","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T13:21:29Z","timestamp":1778160089000},"page":"2323-2337","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Human pancreatic ductal cells from non-diabetic donors function as non-professional antigen-presenting cells upon inflammatory cytokine exposure"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5554-1731","authenticated-orcid":false,"given":"Neslihan","family":"Erdem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7849-3668","authenticated-orcid":false,"given":"David","family":"Arribas-Layton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5780-2042","authenticated-orcid":false,"given":"Heather N.","family":"Zook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7749-9506","authenticated-orcid":false,"given":"Denis","family":"O\u2019Meally","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0640-5437","authenticated-orcid":false,"given":"Jacob","family":"Mares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7755-3154","authenticated-orcid":false,"given":"Janine C.","family":"Quijano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Donohue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1688-4299","authenticated-orcid":false,"given":"Jose A.","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9543-9686","authenticated-orcid":false,"given":"Kevin","family":"Jou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3349-7120","authenticated-orcid":false,"given":"Rupangi C.","family":"Vasavada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7127-6675","authenticated-orcid":false,"given":"Enrique","family":"Montero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-7670","authenticated-orcid":false,"given":"John S.","family":"Kaddis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-3918","authenticated-orcid":false,"given":"Helena","family":"Reijonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5662-9893","authenticated-orcid":false,"given":"Hsun Teresa","family":"Ku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"6746_CR1","doi-asserted-by":"publisher","first-page":"101809","DOI":"10.1016\/j.molmet.2023.101809","volume":"78","author":"EA James","year":"2023","unstructured":"James EA, Joglekar AV, Linnemann AK, Russ HA, Kent SC (2023) The beta cell-immune cell interface in type 1 diabetes (T1D). Mol Metab 78:101809. https:\/\/doi.org\/10.1016\/j.molmet.2023.101809","journal-title":"Mol Metab"},{"issue":"8","key":"6746_CR2","doi-asserted-by":"publisher","first-page":"2881","DOI":"10.1172\/JCI94549","volume":"127","author":"A Pugliese","year":"2017","unstructured":"Pugliese A (2017) Autoreactive T cells in type 1 diabetes. J Clin Investig 127(8):2881\u20132891. https:\/\/doi.org\/10.1172\/JCI94549","journal-title":"J Clin Investig"},{"issue":"8","key":"6746_CR3","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.2337\/db17-1564","volume":"67","author":"RJ Creusot","year":"2018","unstructured":"Creusot RJ, Postigo-Fernandez J, Teteloshvili N (2018) Altered function of antigen-presenting cells in type 1 diabetes: a challenge for antigen-specific immunotherapy? Diabetes 67(8):1481\u20131494. https:\/\/doi.org\/10.2337\/db17-1564","journal-title":"Diabetes"},{"issue":"10","key":"6746_CR4","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s11892-017-0915-y","volume":"17","author":"SC Kent","year":"2017","unstructured":"Kent SC, Mannering SI, Michels AW, Babon JAB (2017) Deciphering the pathogenesis of human type 1 diabetes (T1D) by interrogating T cells from the \u201cscene of the crime.\u201d Curr Diabetes Rep 17(10):95. https:\/\/doi.org\/10.1007\/s11892-017-0915-y","journal-title":"Curr Diabetes Rep"},{"issue":"8","key":"6746_CR5","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.2337\/diabetes.53.8.1987","volume":"53","author":"H Reijonen","year":"2004","unstructured":"Reijonen H, Mallone R, Heninger AK et al (2004) GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes. Diabetes 53(8):1987\u20131994. https:\/\/doi.org\/10.2337\/diabetes.53.8.1987","journal-title":"Diabetes"},{"issue":"8","key":"6746_CR6","doi-asserted-by":"publisher","first-page":"115927","DOI":"10.1016\/j.celrep.2025.115927","volume":"44","author":"PP Nanaware","year":"2025","unstructured":"Nanaware PP, Calvo-Calle JM, Redick SD et al (2025) The antigen presentation landscape of cytokine-stressed human pancreatic islets. Cell Rep 44(8):115927. https:\/\/doi.org\/10.1016\/j.celrep.2025.115927","journal-title":"Cell Rep"},{"issue":"Suppl 22","key":"6746_CR7","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/pedi.12327","volume":"17","author":"J Ilonen","year":"2016","unstructured":"Ilonen J, Kiviniemi M, Lempainen J et al (2016) Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity. Pediatric Diabetes 17(Suppl 22):8\u201316. https:\/\/doi.org\/10.1111\/pedi.12327","journal-title":"Pediatric Diabetes"},{"issue":"11","key":"6746_CR8","doi-asserted-by":"publisher","first-page":"3880","DOI":"10.2337\/db14-0549","volume":"63","author":"T Rodriguez-Calvo","year":"2014","unstructured":"Rodriguez-Calvo T, Ekwall O, Amirian N, Zapardiel-Gonzalo J, von Herrath MG (2014) Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes 63(11):3880\u20133890. https:\/\/doi.org\/10.2337\/db14-0549","journal-title":"Diabetes"},{"issue":"11","key":"6746_CR9","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1016\/j.stem.2021.08.007","volume":"28","author":"S Beyaz","year":"2021","unstructured":"Beyaz S, Chung C, Mou H et al (2021) Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28(11):1922-1935 e1925. https:\/\/doi.org\/10.1016\/j.stem.2021.08.007","journal-title":"Cell Stem Cell"},{"issue":"6","key":"6746_CR10","doi-asserted-by":"publisher","first-page":"G1630","DOI":"10.1152\/ajpgi.00294.2006","volume":"292","author":"I Dotan","year":"2007","unstructured":"Dotan I, Allez M, Nakazawa A, Brimnes J, Schulder-Katz M, Mayer L (2007) Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-\u03b3. Am J Physiol Gastrointest Liver Physiol 292(6):G1630-1640. https:\/\/doi.org\/10.1152\/ajpgi.00294.2006","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"2","key":"6746_CR11","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/s42255-022-00531-x","volume":"4","author":"M Fasolino","year":"2022","unstructured":"Fasolino M, Schwartz GW, Patil AR et al (2022) Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes. Nat Metab 4(2):284\u2013299. https:\/\/doi.org\/10.1038\/s42255-022-00531-x","journal-title":"Nat Metab"},{"issue":"1","key":"6746_CR12","first-page":"128","volume":"65","author":"R Pujol-Borrell","year":"1986","unstructured":"Pujol-Borrell R, Todd I, Doshi M, Gray D, Feldmann M, Bottazzo GF (1986) Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas. Clin Exp Immunol 65(1):128\u2013139","journal-title":"Clin Exp Immunol"},{"issue":"10","key":"6746_CR13","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1136\/gut.34.10.1452","volume":"34","author":"RP Jalleh","year":"1993","unstructured":"Jalleh RP, Gilbertson JA, Williamson RC, Slater SD, Foster CS (1993) Expression of major histocompatibility antigens in human chronic pancreatitis. Gut 34(10):1452\u20131457. https:\/\/doi.org\/10.1136\/gut.34.10.1452","journal-title":"Gut"},{"issue":"4","key":"6746_CR14","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1097\/00006676-199007000-00007","volume":"5","author":"P Bedossa","year":"1990","unstructured":"Bedossa P, Bacci J, Lemaigre G, Martin E (1990) Lymphocyte subsets and HLA-DR expression in normal pancreas and chronic pancreatitis. Pancreas 5(4):415\u2013420. https:\/\/doi.org\/10.1097\/00006676-199007000-00007","journal-title":"Pancreas"},{"issue":"4","key":"6746_CR15","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nrendo.2009.21","volume":"5","author":"DL Eizirik","year":"2009","unstructured":"Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and \u03b2-cell loss in type 1 diabetes. Nat Rev Endocrinol 5(4):219\u2013226. https:\/\/doi.org\/10.1038\/nrendo.2009.21","journal-title":"Nat Rev Endocrinol"},{"issue":"4","key":"6746_CR16","doi-asserted-by":"publisher","first-page":"e14","DOI":"10.1097\/TXD.0000000000000522","volume":"1","author":"M Qi","year":"2015","unstructured":"Qi M, Valiente L, McFadden B et al (2015) The choice of enzyme for human pancreas digestion is a critical factor for increasing the success of islet isolation. Transplant Direct 1(4):e14. https:\/\/doi.org\/10.1097\/TXD.0000000000000522","journal-title":"Transplant Direct"},{"issue":"3","key":"6746_CR17","doi-asserted-by":"publisher","first-page":"109237","DOI":"10.1016\/j.isci.2024.109237","volume":"27","author":"HN Zook","year":"2024","unstructured":"Zook HN, Quijano JC, Ortiz JA et al (2024) Activation of ductal progenitor-like cells from adult human pancreas requires extracellular matrix protein signaling. iScience 27(3):109237. https:\/\/doi.org\/10.1016\/j.isci.2024.109237","journal-title":"iScience"},{"issue":"2","key":"6746_CR18","doi-asserted-by":"publisher","first-page":"103847","DOI":"10.1016\/j.xpro.2025.103847","volume":"6","author":"HN Zook","year":"2025","unstructured":"Zook HN, Quijano JC, Ortiz JA, Donohue C, Erdem N, Ku HT (2025) Protocol to study ductal progenitor-like cells from the adult human pancreas using 3D suspension and methylcellulose-based culture systems. STAR Protoc 6(2):103847. https:\/\/doi.org\/10.1016\/j.xpro.2025.103847","journal-title":"STAR Protoc"},{"issue":"9","key":"6746_CR19","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.2337\/db23-0490","volume":"73","author":"JA Ortiz","year":"2024","unstructured":"Ortiz JA, Ghazalli N, Lopez K et al (2024) Trefoil factor 2 expressed by the murine pancreatic acinar cells is required for the development of islets and for \u03b2-cell function during aging. Diabetes 73(9):1447\u20131461. https:\/\/doi.org\/10.2337\/db23-0490","journal-title":"Diabetes"},{"issue":"Suppl 1","key":"6746_CR20","doi-asserted-by":"publisher","first-page":"2121-LB","DOI":"10.2337\/db25-2121-LB","volume":"74","author":"HTH Vu","year":"2025","unstructured":"Vu HTH, Sun HAN, Sharp S et al (2025) 2121-LB: PanKbase integrated single-cell map\u2014a comprehensive atlas of human pancreatic islets unlocking insights into type 1 and type 2 diabetes. Diabetes 74(Suppl 1):2121-LB. https:\/\/doi.org\/10.2337\/db25-2121-LB","journal-title":"Diabetes"},{"issue":"7","key":"6746_CR21","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.2337\/db19-0058","volume":"68","author":"KH Kaestner","year":"2019","unstructured":"Kaestner KH, Powers AC, Naji A, Atkinson MA (2019) NIH Initiative to improve understanding of the pancreas, islet, and autoimmunity in type 1 diabetes: the Human Pancreas Analysis Program (HPAP). Diabetes 68(7):1394\u20131402. https:\/\/doi.org\/10.2337\/db19-0058","journal-title":"Diabetes"},{"issue":"5","key":"6746_CR22","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/s42255-023-00806-x","volume":"5","author":"AR Patil","year":"2023","unstructured":"Patil AR, Schug J, Naji A, Kaestner KH, Faryabi RB, Vahedi G (2023) Single-cell expression profiling of islets generated by the Human Pancreas Analysis Program. Nat Metab 5(5):713\u2013715. https:\/\/doi.org\/10.1038\/s42255-023-00806-x","journal-title":"Nat Metab"},{"issue":"7","key":"6746_CR23","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671\u2013675. https:\/\/doi.org\/10.1038\/nmeth.2089","journal-title":"Nat Methods"},{"issue":"2","key":"6746_CR24","doi-asserted-by":"publisher","first-page":"525","DOI":"10.2337\/db09-1305","volume":"60","author":"J Mellado-Gil","year":"2011","unstructured":"Mellado-Gil J, Rosa TC, Demirci C et al (2011) Disruption of hepatocyte growth factor\/c-Met signaling enhances pancreatic \u03b2-cell death and accelerates the onset of diabetes. Diabetes 60(2):525\u2013536. https:\/\/doi.org\/10.2337\/db09-1305","journal-title":"Diabetes"},{"issue":"44","key":"6746_CR25","doi-asserted-by":"publisher","first-page":"eadf5238","DOI":"10.1126\/sciadv.adf5238","volume":"9","author":"NG Kondegowda","year":"2023","unstructured":"Kondegowda NG, Filipowska J, Do JS et al (2023) RANKL\/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes. Sci Adv 9(44):eadf5238. https:\/\/doi.org\/10.1126\/sciadv.adf5238","journal-title":"Sci Adv"},{"issue":"4","key":"6746_CR26","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1084\/jem.180.4.1367","volume":"180","author":"CH Chang","year":"1994","unstructured":"Chang CH, Fontes JD, Peterlin M, Flavell RA (1994) Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes. J Exp Med 180(4):1367\u20131374. https:\/\/doi.org\/10.1084\/jem.180.4.1367","journal-title":"J Exp Med"},{"issue":"12","key":"6746_CR27","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/s41577-022-00707-2","volume":"22","author":"N Pishesha","year":"2022","unstructured":"Pishesha N, Harmand TJ, Ploegh HL (2022) A guide to antigen processing and presentation. Nat Rev Immunol 22(12):751\u2013764. https:\/\/doi.org\/10.1038\/s41577-022-00707-2","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"6746_CR28","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nri3405","volume":"13","author":"L Chen","year":"2013","unstructured":"Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13(4):227\u2013242. https:\/\/doi.org\/10.1038\/nri3405","journal-title":"Nat Rev Immunol"},{"key":"6746_CR29","doi-asserted-by":"publisher","first-page":"e00940","DOI":"10.7554\/eLife.00940","volume":"2","author":"J Lee","year":"2013","unstructured":"Lee J, Sugiyama T, Liu Y et al (2013) Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. eLife 2:e00940. https:\/\/doi.org\/10.7554\/eLife.00940","journal-title":"eLife"},{"issue":"3","key":"6746_CR30","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.stemcr.2023.02.001","volume":"18","author":"JC Quijano","year":"2023","unstructured":"Quijano JC, Wedeken L, Ortiz JA et al (2023) Methylcellulose colony assay and single-cell micro-manipulation reveal progenitor-like cells in adult human pancreatic ducts. Stem Cell Rep 18(3):618\u2013635. https:\/\/doi.org\/10.1016\/j.stemcr.2023.02.001","journal-title":"Stem Cell Rep"},{"issue":"6","key":"6746_CR31","first-page":"1763","volume":"148","author":"T Furukawa","year":"1996","unstructured":"Furukawa T, Duguid WP, Rosenberg L, Viallet J, Galloway DA, Tsao MS (1996) Long-term culture and immortalization of epithelial cells from normal adult human pancreatic ducts transfected by the E6E7 gene of human papilloma virus 16. Am J Pathol 148(6):1763\u20131770","journal-title":"Am J Pathol"},{"issue":"8791","key":"6746_CR32","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/0140-6736(92)91061-c","volume":"339","author":"MA Atkinson","year":"1992","unstructured":"Atkinson MA, Kaufman DL, Campbell L et al (1992) Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet 339(8791):458\u2013459. https:\/\/doi.org\/10.1016\/0140-6736(92)91061-c","journal-title":"Lancet"},{"issue":"3","key":"6746_CR33","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.jaut.2005.09.018","volume":"25","author":"V Oling","year":"2005","unstructured":"Oling V, Marttila J, Ilonen J et al (2005) GAD65- and proinsulin-specific CD4+ T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects. J Autoimmun 25(3):235\u2013243. https:\/\/doi.org\/10.1016\/j.jaut.2005.09.018","journal-title":"J Autoimmun"},{"issue":"2","key":"6746_CR34","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/tan.13184","volume":"91","author":"TR Turner","year":"2018","unstructured":"Turner TR, Hayhurst JD, Hayward DR et al (2018) Single molecule real-time DNA sequencing of HLA genes at ultra-high resolution from 126 International HLA and Immunogenetics Workshop cell lines. HLA 91(2):88\u2013101. https:\/\/doi.org\/10.1111\/tan.13184","journal-title":"HLA"},{"issue":"4","key":"6746_CR35","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nri3818","volume":"15","author":"PA Roche","year":"2015","unstructured":"Roche PA, Furuta K (2015) The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 15(4):203\u2013216. https:\/\/doi.org\/10.1038\/nri3818","journal-title":"Nat Rev Immunol"},{"issue":"12","key":"6746_CR36","doi-asserted-by":"publisher","first-page":"R63","DOI":"10.1172\/JCI8476","volume":"104","author":"EJ Novak","year":"1999","unstructured":"Novak EJ, Liu AW, Nepom GT, Kwok WW (1999) MHC class II tetramers identify peptide-specific human CD4+ T cells proliferating in response to influenza A antigen. J Clin Investig 104(12):R63-67. https:\/\/doi.org\/10.1172\/JCI8476","journal-title":"J Clin Investig"},{"issue":"3","key":"6746_CR37","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1210\/endo.136.3.7532577","volume":"136","author":"DS Cram","year":"1995","unstructured":"Cram DS, Faulkner-Jones B, Kun J, Harrison LC (1995) Glutamic acid decarboxylase-67 (GAD67): expression relative to GAD65 in human islets and mapping of autoantibody epitopes. Endocrinology 136(3):1111\u20131119. https:\/\/doi.org\/10.1210\/endo.136.3.7532577","journal-title":"Endocrinology"},{"issue":"4","key":"6746_CR38","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","volume":"24","author":"A Segerstolpe","year":"2016","unstructured":"Segerstolpe A, Palasantza A, Eliasson P et al (2016) Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab 24(4):593\u2013607. https:\/\/doi.org\/10.1016\/j.cmet.2016.08.020","journal-title":"Cell Metab"},{"issue":"12","key":"6746_CR39","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/s0165-6147(98)01270-x","volume":"19","author":"JJ Soghomonian","year":"1998","unstructured":"Soghomonian JJ, Martin DL (1998) Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci 19(12):500\u2013505. https:\/\/doi.org\/10.1016\/s0165-6147(98)01270-x","journal-title":"Trends Pharmacol Sci"},{"issue":"9","key":"6746_CR40","doi-asserted-by":"publisher","first-page":"4465","DOI":"10.4049\/jimmunol.164.9.4465","volume":"164","author":"KC Howland","year":"2000","unstructured":"Howland KC, Ausubel LJ, London CA, Abbas AK (2000) The roles of CD28 and CD40 ligand in T cell activation and tolerance. J Immunol 164(9):4465\u20134470. https:\/\/doi.org\/10.4049\/jimmunol.164.9.4465","journal-title":"J Immunol"},{"issue":"11","key":"6746_CR41","doi-asserted-by":"publisher","first-page":"5530","DOI":"10.4049\/jimmunol.168.11.5530","volume":"168","author":"C Chirathaworn","year":"2002","unstructured":"Chirathaworn C, Kohlmeier JE, Tibbetts SA, Rumsey LM, Chan MA, Benedict SH (2002) Stimulation through intercellular adhesion molecule-1 provides a second signal for t cell activation. J Immunol 168(11):5530\u20135537. https:\/\/doi.org\/10.4049\/jimmunol.168.11.5530","journal-title":"J Immunol"},{"issue":"4","key":"6746_CR42","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.4049\/jimmunol.152.4.1523","volume":"152","author":"M Cayabyab","year":"1994","unstructured":"Cayabyab M, Phillips JH, Lanier LL (1994) CD40 preferentially costimulates activation of CD4+ T lymphocytes. J Immunol 152(4):1523\u20131531","journal-title":"J Immunol"},{"issue":"1","key":"6746_CR43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1023\/A:1014256417651","volume":"22","author":"H Bour-Jordan","year":"2002","unstructured":"Bour-Jordan H, Bluestone JA (2002) CD28 function: a balance of costimulatory and regulatory signals. J Clin Immunol 22(1):1\u20137. https:\/\/doi.org\/10.1023\/A:1014256417651","journal-title":"J Clin Immunol"},{"issue":"2","key":"6746_CR44","doi-asserted-by":"publisher","first-page":"L274","DOI":"10.1152\/ajplung.00004.2005","volume":"289","author":"H Debbabi","year":"2005","unstructured":"Debbabi H, Ghosh S, Kamath AB et al (2005) Primary type II alveolar epithelial cells present microbial antigens to antigen-specific CD4+ T cells. Am J Physiol Lung Cell Mol Physiol 289(2):L274-279. https:\/\/doi.org\/10.1152\/ajplung.00004.2005","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"6746_CR45","doi-asserted-by":"publisher","first-page":"446","DOI":"10.3389\/fimmu.2015.00446","volume":"6","author":"S Hirosue","year":"2015","unstructured":"Hirosue S, Dubrot J (2015) Modes of antigen presentation by lymph node stromal cells and their immunological implications. Front Immunol 6:446. https:\/\/doi.org\/10.3389\/fimmu.2015.00446","journal-title":"Front Immunol"},{"issue":"6","key":"6746_CR46","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1016\/s0016-5085(99)70508-1","volume":"116","author":"PA Knolle","year":"1999","unstructured":"Knolle PA, Schmitt E, Jin S et al (1999) Induction of cytokine production in naive CD4+ T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116(6):1428\u20131440. https:\/\/doi.org\/10.1016\/s0016-5085(99)70508-1","journal-title":"Gastroenterology"},{"issue":"1","key":"6746_CR47","doi-asserted-by":"publisher","first-page":"5567","DOI":"10.1038\/s41467-024-49724-w","volume":"15","author":"MM Maestas","year":"2024","unstructured":"Maestas MM, Ishahak M, Augsornworawat P et al (2024) Identification of unique cell type responses in pancreatic islets to stress. Nat Commun 15(1):5567. https:\/\/doi.org\/10.1038\/s41467-024-49724-w","journal-title":"Nat Commun"},{"key":"6746_CR48","doi-asserted-by":"publisher","first-page":"1381319","DOI":"10.3389\/fimmu.2024.1381319","volume":"15","author":"A Munoz Garcia","year":"2024","unstructured":"Munoz Garcia A, Juksar J, Groen N, Zaldumbide A, de Koning E, Carlotti F (2024) Single-cell transcriptomics reveals a role for pancreatic duct cells as potential mediators of inflammation in diabetes mellitus. Front Immunol 15:1381319. https:\/\/doi.org\/10.3389\/fimmu.2024.1381319","journal-title":"Front Immunol"},{"issue":"2","key":"6746_CR49","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1006\/bbrc.1996.1655","volume":"228","author":"A Smismans","year":"1996","unstructured":"Smismans A, Ling Z, Pipeleers D (1996) Damaged rat \u03b2 cells discharge glutamate decarboxylase in the extracellular medium. Biochem Biophys Res Commun 228(2):293\u2013297. https:\/\/doi.org\/10.1006\/bbrc.1996.1655","journal-title":"Biochem Biophys Res Commun"},{"issue":"7","key":"6746_CR50","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1007\/s00125-021-05453-z","volume":"64","author":"E Korpos","year":"2021","unstructured":"Korpos E, Kadri N, Loismann S et al (2021) Identification and characterisation of tertiary lymphoid organs in human type 1 diabetes. Diabetologia 64(7):1626\u20131641. https:\/\/doi.org\/10.1007\/s00125-021-05453-z","journal-title":"Diabetologia"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06746-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06746-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06746-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T19:00:23Z","timestamp":1782586823000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06746-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["6746"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06746-x","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"2 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We are grateful for the generosity of the organ donors and their families who made this work possible. We are thankful for services provided by the Southern California Islet Cell Resource Center (SC-IRC), Histocompatibility (HLA) and Immunogenetics Laboratory, Analytical Flow Cytometry, Light Microscopy Digital Imaging, Integrative Genomics, Biostatistics and High Performance Research Computing Center (HPRCC) at the City of Hope. Some figure panels were created with BioRender.com. Data shown in Fig.\n                      \n                      j,k were acquired from the database (\n                      \n                      ) of the Human Pancreas Analysis Program (HPAP; RRID:SCR_016202) [\n                      \n                      ]. HPAP is part of the Human Islet Research Network (HIRN; RRID:SCR_014393) consortium (UC4-DK112217, U01-DK123594, UC4-DK112232 and U01-DK123716). Figure\n                      \n                      j,k also contained data from the Pancreas Knowledgebase Program (PanKbase;\n                      \n                      ), an initiative supported by NIDDK U24DK138515, U24DK138512 and supplemental funds from the NIH Office of Data Science Strategies. PanKbase is also a part of the HIRN, and includes data derived from human pancreatic islets and\/or other resources provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP; RRID:SCR _014387) at City of Hope, NIH grant no. U24DK098085.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, HTK (hku@coh.org). The bulk mRNA-seq dataset is deposited to the Gene Expression Omnibus (GEO;\n                      \n                      ) with accession number GSE309294. The PanKbase Seurat object for publicly available scRNA-seq datasets [\n                      \n                      ,\n                      \n                      ,\n                      \n                      ] is archived at\n                      \n                      and code to reproduce the associated figures is available at\n                      \n                      .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Microsoft Copilot was used for language enhancement. Claude (Anthropic) was used to develop R code for analysis of publicly available scRNA-seq and to assist with interpretation. All AI-generated content was carefully reviewed and edited by the authors, who take full responsibility for the final manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration of generative AI and AI-assisted technologies"}},{"value":"Open access funding provided by SCELC, Statewide California Electronic Library Consortium. Research reported in this publication was supported, in part, by the National Institutes of Health grants to HTK (R01DK099734 and R01DK134652) and the City of Hope Research Facilities (P30CA33572). Support from the H.N. & Frances C. Berger Foundation Fellowship (NE), the Dr. Norman and Melinda Payson Graduate Student Fellowship (NE), a postdoctoral fellowship from the California Institute for Regenerative Medicine (EDU4-12772, HNZ), the Wanek Family Project for Type 1 Diabetes (HTK), an anonymous donor S.S. (HTK) and The Margie & Robert E. Petersen Foundation (HR) is also gratefully acknowledged. This manuscript was written with use of resources and\/or funding provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported Human Islet Research Network (HIRN; Research Resource Identifier [RRID]: SCR_014393) (\n                      \n                      ), including U24DK104162 to DO and JSK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"HTK is an inventor of a patent, no. 9,783,784, titled \u2018Methods for establishing and improving the survival of a population of pancreatic progenitor or stem cells\u2019. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors' relationships and activities"}},{"value":"NE, HR and HTK designed the study. The methodology was developed by NE, DA-L, DO, RCV, EM, JSK, HR and HTK. The data acquisition, validation and interpretation was carried out by NE, DA-L, DO, HNZ, JCQ, JAO, CD, JM and KJ. Resources were provided by HR and HTK. The original draft was prepared by NE and HTK. All authors provided substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of the data, drafted or reviewed the article critically for intellectual content, and final approval of the version to be published. Funding for the project was acquired by HTK, HR, NE and HNZ. HTK is the guarantor of this work.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}