tRNA-derived fragments in T lymphocyte–beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice

作者：Flora Brozzi, Cécile Jacovetti, Cristina Cosentino, Véronique Menoud, Kejing Wu, Mustafa Bilal Bayazit, Baroj Abdulkarim, Christian Iseli, Nicolas Guex, Claudiane Guay, Romano Regazzi · 发表于：Diabetologia · 年份：2024 · DOI：10.1007/s00125-024-06207-3 · 被引用次数：13 · 研究领域：RNA modifications and cancer、Diabetes and associated disorders、RNA and protein synthesis mechanisms

Abstract Aims/hypothesis tRNAs play a central role in protein synthesis. Besides this canonical function, they were recently found to generate non-coding RNA fragments (tRFs) regulating different cellular activities. The aim of this study was to assess the involvement of tRFs in the crosstalk between immune cells and beta cells and to investigate their contribution to the development of type 1 diabetes. Methods Global profiling of the tRFs present in pancreatic islets of 4- and 8-week-old NOD mice and in extracellular vesicles released by activated CD4 + T lymphocytes was performed by small RNA-seq. Changes in the level of specific fragments were confirmed by quantitative PCR. The transfer of tRFs from immune cells to beta cells occurring during insulitis was assessed using an RNA-tagging approach. The functional role of tRFs increasing in beta cells during the initial phases of type 1 diabetes was determined by overexpressing them in dissociated islet cells and by determining the impact on gene expression and beta cell apoptosis. Results We found that the tRF pool was altered in the islets of NOD mice during the initial phases of type 1 diabetes. Part of these changes were triggered by prolonged exposure of beta cells to proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) while others resulted from the delivery of tRFs produced by CD4 + T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4 + /CD25 − T c...