Project description:T cells infiltrate pancreatic islets during the progression of type 1 diabetes (T1D) but their differentiation states have not been completely defined. We used unbiased single-cell RNA sequencing analyses to gain further insight into the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice.
Project description:Pancreas specific deletion of the Haster promoter region results in a variegated phenotype in pancreatic islets with overexpression or silencing of the Hnf1a gene. To determine the transcriptional consequence of the overexpression or silencing of Hnf1a is islet cells from the Haster pKO mice (Haster loxP/loxP;Pdx1-Cre), we performed scRNA-seq of pancreatic islets from control and adult female Haster pKO mice.
Project description:In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing β cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of β-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined. Here we used single-cell RNA sequencing to gain further insight into the phenotypic complexity of islet-infiltrating CD8 T cells in NOD mice. We identified two functionally distinct subsets of activated CD8 T cells, CD44highTCF1+CXCR6- and CD44highTCF1-CXCR6+, in islets of prediabetic NOD mice. Compared to CD44highTCF1+CXCR6- CD8 T cells, the CD44highTCF1-CXCR6+ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44highTCF1+CXCR6- CD8 T cells, through continuous generation of the CD44highTCF1-CXCR6+ subset, were more capable than the latter population to promote insulitis and the development of T1D. We further showed that direct interleukin-27 (IL-27) signaling in CD8 T cells promoted the generation of terminal effectors from the CD44highTCF1+CXCR6- population. These results indicate that islet CD44highTCF1+CXCR6- CD8 T cells are a progenitor-like subset with self-renewing capacity and under an IL-27 controlled mechanism they differentiate into the CD44highTCF1-CXCR6+ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.
Project description:To gain insights into how pancreatic cells are programmed in vivo, we profiled Ring1b in embryonic stem cells and pancreatic islets
Project description:To gain insights into how pancreatic cells are programmed in vivo, we profiled RNA expression in pancreatic islets of pancreatic Ring1b conditional KO mice (conditional using a pancreas specfic Cre; Pdx1-Cre) and their littermate controls
Project description:In this study, we achieved integrated transcriptomic and proteomic profiles of GK islets in a time-course fashion at different stages of T2D. Subsequent bioinformatics analysis revealed the chronological order of T2D-related molecular events during the deterioration of pancreatic islets. Our large quantitative dataset provide a valuable resource to obtain a comprehensive picture of the mechanisms responsible for islet dysfunction and to identify potential interventions to prevent beta-cell failure in human T2D.
Project description:Pancreatic islet beta cell heterogeneity has been identified, which plays a pivotal role in the pathological alterations of pancreatic islets in type 2 diabetes (T2D) mice. However, pathological alterations of beta cells in type 2 diabetes (T2D) mice remain to be investigated. We isolated pancreatic islets from the control and T2D mice and conducted scRNA-seq analysis using the 10x Genomics platform. Pathological alterations of beta cells in T2D were also explored.