Role of tRNA-derived fragments in the cross-talk between immune cells and beta cells during type 1 diabetes pathogenesis (tRF overexpression)
Transfer RNAs (tRNAs) play a central and well recognized role in protein synthesis. Recent studies revealed that these molecules can be cleaved to generate tRNA fragments (tRFs) with regulatory functions. Here, we studied the contribution of tRFs to pancreatic ß-cell loss during the initial phases of type 1 diabetes (T1D), an autoimmune disorder characterized by the invation of immune cells in the pancreas and progressive loss of insulin-secreting cells. Small RNA-profiling showed that the pool of tRFs present in pancreatic ß-cells is altered in non-obese diabetic (NOD) mice, a mouse model used to study T1D. We found that part of these changes is triggered by the exposure of ß-cells to proinflammatory cytokines released during the autoimmune reaction while others result from the direct transfer of tRFs from autoreactive T lymphocytes to insulin-secreting cells via extracellular vesicles. Indeed, using an RNA-tagging approach, we could demonstrate that a group of tRFs are transferred in vivo in from CD4+CD25- T lymphocytes to pancreatic ß-cells, upon T cell adoptive transfer in NOD scid mice. Morevoer, the up-regulation of selected tRFs associated with the autoimmune reaction triggers ß-cell apoptosis and gene expression changes that affect the immune regulatory capacity of ß-cells. Our data point to tRFs as novel players in type 1 diabetes and potentially in other autoimmune disorders. Overall design: Using NOD mice as a model of T1D, we detected a specific tRF signature in islet cells during the initial phases of the disease. Through an RNA-tagging approach we were able to show both in vitro and in vivo that a fraction of the tRFs displaying elevated levels during insulitis are directly transferred from autoreactive T cells to ß-cells via EVs. To gain more insights into the role of the tRFs transferred in ß-cells, we performedbulk RNA-seq analysis in mouse islet cells overexpressing mimic oligonucleotides of LysCTT-5', PheGAA-5' and SerGCT-3', for 48h. A scramble sequence of the mimic tRFs was used in the control condition (CT).