{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:37:40Z","timestamp":1792802260195,"version":"4.5.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:00:00Z","timestamp":1792800000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:00:00Z","timestamp":1792800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biomed"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Type 1 diabetes mellitus (T1DM) is characterized by the destruction of pancreatic \u03b2-cells, in which the dysfunction of regulatory T cells (Tregs) contributes to impaired immune tolerance. However, Treg heterogeneity remains incompletely understood, which limits the effectiveness of current therapies. Here, we have integrated transcriptome, flow cytometry, glycemic correlation, and cross-model validation to characterize the dysregulation of Tregs and effector T cells (Teffs) in a\u00a0streptozotocin (STZ)-induced T1DM mouse model. Tregs exhibited a proliferative, effector-like, unstable lineage, and\u00a0metabolic reprogramming features, marked by increased\n                    <jats:italic>Melk<\/jats:italic>\n                    ,\n                    <jats:italic>Prf1<\/jats:italic>\n                    ,\n                    <jats:italic>Gzma<\/jats:italic>\n                    and\n                    <jats:italic>Hk2<\/jats:italic>\n                    , and decreased expression of\u00a0\n                    <jats:italic>Tnfsf15<\/jats:italic>\n                    ,\n                    <jats:italic>Irak3<\/jats:italic>\n                    and\n                    <jats:italic>Zeb2<\/jats:italic>\n                    in T1DM, and alterations in the transcription-factor networks involving\n                    <jats:italic>Nfatc2<\/jats:italic>\n                    ,\n                    <jats:italic>Elk1<\/jats:italic>\n                    , and\n                    <jats:italic>Ahr<\/jats:italic>\n                    . Flow cytometry further revealed that the frequency of splenic Tregs was significantly increased, accompanied by broad upregulation of programmed cell death protein\u00a01 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), lymphocyte-activation gene 3 (LAG3), and\u00a0T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3). Meanwhile, expression of glycoprotein A repetitions predominant (GARP) and latency-associated peptide (LAP) was decreased, whereas interleukin (IL)-\u200917 and interferon-\u03b3 (IFN-\u03b3) secretion were increased, suggesting a Treg phenotype with high checkpoint expression and inflammatory features. Cross-model analyses identified concordant IL-15-, IL-36\u00a0A-, E2F-, and metabolic programs across the C57BL\/6, non-obese diabetic (NOD), and human datasets, including shared genes\n                    <jats:italic>Smad3<\/jats:italic>\n                    ,\n                    <jats:italic>Mki67<\/jats:italic>\n                    , and\n                    <jats:italic>Cxcr4<\/jats:italic>\n                    . Teffs also displayed a hyperactivated but transcriptionally imbalanced phenotype in T1DM. Collectively, our findings reveal transcriptional and phenotypic alterations in Tregs and Teffs, providing new insights into T-cell dysregulation and potentially informing the development of Treg-based immunotherapies in T1DM.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00636-9","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:02:21Z","timestamp":1792796541000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptional and phenotypic alterations of regulatory and effector T cells in type 1 diabetes mellitus"],"prefix":"10.1186","volume":"7","author":[{"given":"Yutong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhui","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyad","family":"Elkord","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,24]]},"reference":[{"issue":"3","key":"636_CR1","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/S2213-8587(19)30412-7","volume":"8","author":"JM Norris","year":"2020","unstructured":"Norris JM, Johnson RK, Stene LC. Type 1 diabetes\u2014early life origins and changing epidemiology. Lancet Diabetes Endocrinol. 2020;8(3):226\u201338. https:\/\/doi.org\/10.1016\/S2213-8587(19)30412-7.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"10","key":"636_CR2","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/S2213-8587(22)00218-2","volume":"10","author":"GA Gregory","year":"2021","unstructured":"Gregory GA, Robinson TIG, Linklater SE, Wang F, Colagiuri S, de Beaufort C, et al. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol. 2021;10(10):741\u201360. https:\/\/doi.org\/10.1016\/S2213-8587(22)00218-2.","journal-title":"Lancet Diabetes Endocrinol"},{"key":"636_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2025.112277","volume":"225","author":"GD Ogle","year":"2025","unstructured":"Ogle GD, Wang F, Haynes A, Gregory GA, King TW, Deng K, et al. Global type 1 diabetes prevalence, incidence, and mortality estimates 2025: results from the International Diabetes Federation Atlas, 11th Edition, and the T1D Index Version 3.0. Diabetes Res Clin Pract. 2025;225:112277. https:\/\/doi.org\/10.1016\/j.diabres.2025.112277.","journal-title":"Diabetes Res Clin Pract"},{"issue":"Suppl 1","key":"636_CR4","doi-asserted-by":"publisher","first-page":"S181","DOI":"10.2337\/dc25-S009","volume":"48","author":"NA ElSayed","year":"2025","unstructured":"ElSayed NA, McCoy RG, Aleppo G, Bajaj M, Balapattabi K, Beverly EA, et al. Pharmacologic approaches to glycemic treatment: standards of care in diabetes\u20142025. 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