TCL1A in naïve B cells as a therapeutic target for type 1 diabetes

作者：Siweier Luo, Lína Zhang, Chunfang Wei, Chipeng Guo, Zhe Meng, Honghui Zeng, Lele Hou, Le Wang, Zulin Liu, Yufei Du, Shiyu Tan, Yating Zhang, Xiaoding Xu, Liyang Liang, Yiming Zhou · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105593 · 被引用次数：6 · 研究领域：Diabetes and associated disorders、T-cell and B-cell Immunology、Pancreatic function and diabetes

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by "self" immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different populations of B cells, particularly in the early stages of T1D, has not been fully elucidated. METHODS: In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to investigate immune cell populations in patients with newly diagnosed T1D, their relative controls and age-matched healthy controls. Phosphoprotein microarray analysis was employed to investigate changes in protein phosphorylation in B cells. Furthermore, we developed a siRNA-based nanomedicine and evaluated its therapeutic potential in the NOD mouse. The integration of scRNA-seq, flow cytometry, phosphoprotein microarrays, and functional assays established a robust framework for understanding and targeting B cell-mediated autoimmunity in T1D. FINDINGS: Using single-cell RNA sequencing, we discovered that patients with T1D exhibited increased humoural immunity in the early stage of T1D. Specifically, the population of naïve B cells increased in patients with newly diagnosed T1D who expressed elevated levels of the AKT kinase coactivator TCL1A. Using a protein phosphorylation microarray, we confirmed that TCL1A knockdown specifically impaired AKT2 phosphorylation and affected B cell survival and prolifer...