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As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, and islet macrophages are thought to play a role in the pathogenesis of type 1 diabetes, we sought to understand the impact of islet amyloid on islet macrophages and beta cell autoimmunity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single-cell RNA-seq of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). The role of islet amyloid in autoimmune diabetes and antigen presentation was assessed in hIAPP-expressing NOD mice and in antigen-presenting cells ex vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MHC class II (MHCII) antigen presentation genes were strongly downregulated in islet macrophages during islet amyloid formation. NOD mice expressing an hIAPP transgene had delayed diabetes relative to littermate controls (median onset 30.3 vs 19.5 weeks,\n                      <jats:italic>p<\/jats:italic>\n                      =0.016). Likewise, physiological expression of hIAPP by genetic knockin also delayed diabetes in NOD mice relative to littermate controls (median onset 28.2 vs 18.0 weeks,\n                      <jats:italic>p<\/jats:italic>\n                      =0.049), corresponding with decreased markers of antigen presentation and activation, as well as decreased immune cell infiltration in islets. Adoptive transfer studies showed that systemic autoimmune function remained intact and beta cells from hIAPP transgenic mice did not evade immune recognition by diabetogenic T cells, collectively indicating the protection from diabetes was mediated by decreased antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with islet amyloid polypeptide (IAPP) aggregates decreased MHCII surface expression and diminished antigen-specific T cell activation through a phagocytosis-dependent mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Collectively, our data reveal a novel role for IAPP aggregates in decreasing MHCII antigen presentation and show that despite the well-established proinflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts beta cell autoimmunity and delays diabetes in NOD mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06622-0","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T01:43:30Z","timestamp":1766367810000},"page":"987-999","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Islet amyloid disrupts MHC class II antigen presentation and delays autoimmune diabetes in NOD mice"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0976-2656","authenticated-orcid":false,"given":"Heather C.","family":"Denroche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Velghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imelda","family":"Suen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Stanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Nackiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiro","family":"Komba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek L.","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Soukhatcheva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9262-0586","authenticated-orcid":false,"given":"C. 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Nat Commun 14(1):6294. https:\/\/doi.org\/10.1038\/s41467-023-41986-0","journal-title":"Nat Commun"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06622-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-025-06622-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06622-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T15:51:55Z","timestamp":1772553115000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-025-06622-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,22]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["6622"],"URL":"https:\/\/doi.org\/10.1007\/s00125-025-06622-0","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,22]]},"assertion":[{"value":"8 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"hIAPP knockin mice were provided in kind from S. Kahn (University of Washington Diabetes Institute, USA). LNPs were provided in kind by Integrated Nanotherapeutics. RNA-seq was performed by the BRC-Seq Next Gen Sequencing Core (University of British Columbia, Canada). The authors wish to thank D. Wu (University of British Columbia, Canada) and L. Xu (BC Children\u2019s Hospital Research Institute, Canada) for providing expertise and assistance with panel design, flow cytometry and FACS. The authors also wish to thank S. Skovs\u00f8 (Valkyrie Life Sciences, Vancouver, Canada) who facilitated manuscript drafting and editing as well as data analysis and figure and schematic overview generation.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"RNA-seq data will be deposited in the Gene Expression Omnibus database upon publication. Any data that support the findings of this study are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"HCD was supported by a Postdoctoral Fellowship and Advanced Postdoctoral Fellowship from Breakthrough T1D (formerly JDRF) (3-PDF-2014-191-A-N and 3-APF-2018-586-A-N). CBV is supported by an Investigatorship from the BC Children\u2019s Hospital Research Institute and the Irving K. Barber Chair in Diabetes Research. This work was supported by grants from the Canadian Institutes of Health Research to CBV (PJT-156449 and PJT-165943). Core funding was provided by the BC Children\u2019s Hospital Foundation through the Canucks for Kids Fund Childhood Diabetes Laboratories.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"HD, SC and CBV are cofounders of Integrated Nanotherapeutics. HD took on employment at Integrated Nanotherapeutics after her postdoctoral fellowship and completion of the experiments in this manuscript. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author\u2019s relationships and activities"}},{"value":"All authors reviewed the manuscript critically for intellectual content and approved the final version to be published. HD conceived, designed and conducted the research in this manuscript, analysed the majority of the data and wrote the manuscript. LS, IS, DLD and GS acquired in vivo mouse data. VN conducted proliferation assays and BMDC experiments. DN and MK assisted with scRNA-seq experiments and JV conducted the scRNA-seq analysis. SC designed and formulated LNPs for Ova immunisation and Integrated Nanotherapeutics provided these LNPs in kind. CBV contributed to the conception, design and interpretation of the data, and is the guarantor of the data.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}