{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:56:11Z","timestamp":1790283371076,"version":"4.1.0"},"reference-count":24,"publisher":"American Diabetes Association","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Italian Ministry of Education, University and Research","award":["program Departments of Excellence 2018\u20132022"],"award-info":[{"award-number":["program Departments of Excellence 2018\u20132022"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Type 1 diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell\u2013mediated immune attack of pancreatic \u03b2-cells. There are no biomarkers to effectively diagnose autoimmunity before disease onset and clinical symptom development. Here, we applied deep multiparametric immunophenotyping to compare immune landscapes in 38 patients with new-onset T1D, 24 siblings, and 18 healthy control participants (HCs). Patients with T1D underwent clinical and metabolic evaluations. Immune populations in fresh whole-blood samples were analyzed using a panel of 26 antibodies, detecting 39 different cell populations. Memory regulatory T cells (memory Tregs) were significantly increased in patients with T1D (P &amp;lt; 0.05) and their siblings (P &amp;lt; 0.01) compared with HCs but not between patients with T1D and siblings. Memory Tregs were associated with disease status and age in multivariable analysis. There was a positive correlation between age and memory Tregs in the HC and sibling groups but not in patients with T1D. Baseline memory Treg levels in siblings resembled those of patients with T1D. These findings highlight the existence of an age-independent, disease-specific immune fingerprint that could serve as a minimally invasive biomarker for early diagnosis and personalized immunotherapy. Further studies using functional and single-cells analysis are needed to confirm memory Tregs as a pathogenic trait.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>There are more memory regulatory T cells (Tregs) in individuals with type 1 diabetes (T1D) and siblings than in healthy control (HC) individuals. Individuals with T1D and their siblings share an immunological profile, with siblings displaying an intermediate phenotype that overlaps with both T1D and HC individuals. Memory Tregs increased with age in HC individuals and siblings but not in individuals with T1D. Diabetic ketoacidosis status had no impact on immune cell populations in patients with T1D.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0161","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T18:20:32Z","timestamp":1771870832000},"page":"676-682","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":5,"title":["Memory Regulatory T Cells as a Biomarker of Early Type 1 Diabetes"],"prefix":"10.2337","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-6305","authenticated-orcid":false,"given":"Davide","family":"Raineri","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Center for Translational Research on Autoimmune and Allergic Diseases, University of Eastern Piedmont 2 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Savastio","sequence":"additional","affiliation":[{"name":"Division of Paediatrics, Department of Health Sciences, University of Eastern Piedmont 3 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simonetta","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Division of Paediatrics, Department of Health Sciences, University of Eastern Piedmont 3 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenza","family":"Scotti","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Eastern Piedmont 4 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Barbero-Mazzucca","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Center for Translational Research on Autoimmune and Allergic Diseases, University of Eastern Piedmont 2 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Cappellano","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Center for Translational Research on Autoimmune and Allergic Diseases, University of Eastern Piedmont 2 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9660-5335","authenticated-orcid":false,"given":"Flavia","family":"Prodam","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Endocrinology, Department of Translational Medicine, University of Eastern Piedmont 5 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Division of Paediatrics, Department of Health Sciences, University of Eastern Piedmont 3 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4173-146X","authenticated-orcid":false,"given":"Ivana","family":"Rabbone","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Division of Paediatrics, Department of Health Sciences, University of Eastern Piedmont 3 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-1087","authenticated-orcid":false,"given":"Annalisa","family":"Chiocchetti","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont 1 , Novara, Italy"},{"name":"Center for Translational Research on Autoimmune and Allergic Diseases, University of Eastern Piedmont 2 , Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"2026061712270873000_B1","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1016\/S0140-6736(18)31320-5","article-title":"Type 1 diabetes","volume":"391","author":"DiMeglio","year":"2018","journal-title":"Lancet"},{"key":"2026061712270873000_B2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.2337\/db12-0315","article-title":"Human \u03b2-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity","volume":"62","author":"Knight","year":"2013","journal-title":"Diabetes"},{"key":"2026061712270873000_B3","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/icb.2015.89","article-title":"Perforin facilitates beta cell killing and regulates autoreactive CD8+ T-cell responses to antigen in mouse models of type 1 diabetes","volume":"94","author":"Trivedi","year":"2016","journal-title":"Immunol Cell Biol"},{"key":"2026061712270873000_B4","first-page":"2724","article-title":"Methods to assess beta cell death mediated by cytotoxic T lymphocytes","volume":"16","author":"Chen","year":"2011","journal-title":"J Vis Exp"},{"key":"2026061712270873000_B5","doi-asserted-by":"crossref","first-page":"4644","DOI":"10.4049\/jimmunol.1100272","article-title":"Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function","volume":"188","author":"Garg","year":"2012","journal-title":"J Immunol"},{"key":"2026061712270873000_B6","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.2337\/db15-0516","article-title":"Natural variation in interleukin-2 sensitivity influences regulatory T-cell frequency and function in individuals with long-standing type 1 diabetes","volume":"64","author":"Yang","year":"2015","journal-title":"Diabetes"},{"key":"2026061712270873000_B7","doi-asserted-by":"crossref","first-page":"10074","DOI":"10.1038\/s41598-018-28423-9","article-title":"CTLA-4 +49\u2009G\/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function","volume":"8","author":"Chen","year":"2018","journal-title":"Sci Rep"},{"key":"2026061712270873000_B8","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00125-003-1089-5","article-title":"The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure","volume":"46","author":"Roep","year":"2003","journal-title":"Diabetologia"},{"key":"2026061712270873000_B9","doi-asserted-by":"crossref","first-page":"3940739","DOI":"10.1155\/2019\/3940739","article-title":"Interplay between the adaptive immune system and insulin resistance in weight loss induced by bariatric surgery","volume":"2019","author":"Villarreal-Calder\u00f3n","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"2026061712270873000_B10","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/cei.13332","article-title":"A study of 51 subtypes of peripheral blood immune cells in newly diagnosed young type 1 diabetes patients","volume":"198","author":"Oras","year":"2019","journal-title":"Clin Exp Immunol"},{"key":"2026061712270873000_B11","doi-asserted-by":"crossref","first-page":"e170767","DOI":"10.1172\/jci.insight.170767","article-title":"Human immune phenotyping reveals accelerated aging in type 1 diabetes","volume":"8","author":"Shapiro","year":"2023","journal-title":"JCI Insight"},{"key":"2026061712270873000_B12","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1007\/s00125-021-05647-5","article-title":"Characterising the age-dependent effects of risk factors on type 1 diabetes progression","volume":"65","author":"So","year":"2022","journal-title":"Diabetologia"},{"key":"2026061712270873000_B13","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41581-023-00720-1","article-title":"Pathogenesis of autoimmune disease","volume":"19","author":"Pisetsky","year":"2023","journal-title":"Nat Rev Nephrol"},{"key":"2026061712270873000_B14","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/pedi.13406","article-title":"ISPAD clinical practice consensus guidelines 2022: diabetic ketoacidosis and hyperglycemic hyperosmolar state","volume":"23","author":"Glaser","year":"2022","journal-title":"Pediatr Diabetes"},{"key":"2026061712270873000_B15","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.2337\/dc23-S002","article-title":"2. Classification and diagnosis of diabetes: Standards of Care in Diabetes\u20142023","volume":"46","author":"ElSayed","year":"2023","journal-title":"Diabetes Care"},{"key":"2026061712270873000_B16","doi-asserted-by":"crossref","first-page":"100942","DOI":"10.1016\/j.bbih.2024.100942","article-title":"Deep immunophenotyping of circulating immune cells in major depressive disorder patients reveals immune correlates of clinical course and treatment response","volume":"43","author":"Stolfi","year":"2025","journal-title":"Brain Behav Immun Health"},{"key":"2026061712270873000_B17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mam.2014.12.004","article-title":"Immunogenetics of type 1 diabetes mellitus","volume":"42","author":"Morran","year":"2015","journal-title":"Mol Aspects Med"},{"key":"2026061712270873000_B18","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/1753-0407.12870","article-title":"Altered expression of CD39 on memory regulatory T cells in type 1 diabetes patients","volume":"11","author":"Jin","year":"2019","journal-title":"J Diabetes"},{"key":"2026061712270873000_B19","doi-asserted-by":"crossref","first-page":"e142680","DOI":"10.1172\/jci.insight.142680","article-title":"Exhausted-like CD8+ T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects","volume":"6","author":"Diggins","year":"2021","journal-title":"JCI Insight"},{"key":"2026061712270873000_B20","doi-asserted-by":"crossref","first-page":"eabc8980","DOI":"10.1126\/scitranslmed.abc8980","article-title":"Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals","volume":"13","author":"Sims","year":"2021","journal-title":"Sci Transl Med"},{"key":"2026061712270873000_B21","doi-asserted-by":"crossref","first-page":"e73709","DOI":"10.7554\/eLife.73709","article-title":"A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes","volume":"11","author":"Chu","year":"2022","journal-title":"Elife"},{"key":"2026061712270873000_B22","doi-asserted-by":"crossref","first-page":"1335435","DOI":"10.3389\/fendo.2024.1335435","article-title":"Gene-environment interaction in the pathophysiology of type 1 diabetes","volume":"15","author":"Mittal","year":"2024","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026061712270873000_B23","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1084\/jem.20040165","article-title":"Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF\u03b1 therapy","volume":"200","author":"Ehrenstein","year":"2004","journal-title":"J Exp Med"},{"key":"2026061712270873000_B24","doi-asserted-by":"crossref","first-page":"940705","DOI":"10.3389\/fimmu.2022.940705","article-title":"The dark side of Tregs during aging","volume":"13","author":"Palatella","year":"2022","journal-title":"Front Immunol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/75\/4\/676\/857614\/db250161.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/75\/4\/676\/857614\/db250161.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:27:15Z","timestamp":1781713635000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/75\/4\/676\/164507\/Memory-Regulatory-T-Cells-as-a-Biomarker-of-Early"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":24,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2,23]]},"published-print":{"date-parts":[[2026,4,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db25-0161","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]}}}