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Life sciences · Journal article
Molecular Biomedicine · October 23, 2026
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Abstract Type 1 diabetes mellitus (T1DM) is characterized by the destruction of pancreatic β-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 streptozotocin (STZ)-induced T1DM mouse model. Tregs exhibited a proliferative, effector-like, unstable lineage, and metabolic reprogramming features, marked by increased Melk, Prf1, Gzma and Hk2, and decreased expression of Tnfsf15, Irak3 and Zeb2 in T1DM, and alterations in the transcription-factor networks involving Nfatc2, Elk1, and Ahr. Flow cytometry further revealed that the frequency of splenic Tregs was significantly increased, accompanied by broad upregulation of programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), lymphocyte-activation gene 3 (LAG3), and T-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)- 17 and interferon-γ (IFN-γ) secretion were increased, suggesting a Treg phenotype with high checkpoint expression and inflammatory features. Cross-model analyses identified concordant IL-15-, IL-36 A-, E2F-, and metabolic programs across the C57BL/6, non-obese diabetic (NOD), and human datasets, including shared genes Smad3, Mki67, and Cxcr4. 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.