Role of small intronic RNAs in the crosstalk between immune cells and β-cells during type 1 diabetes development.

Abstract

Small non-coding RNAs, such as microRNAs and tRNA-derived fragments, are key regulators of cellular processes, but the functions of small intronic RNAs (sinRNAs), a recently identified RNA class, remain largely unknown. Here, we report that two sinRNAs, sinR-D and sinR-T, are upregulated in pancreatic β-cells of NOD mice, a well-established model of type 1 diabetes. Using in vivo RNA-tagging, we demonstrate that these sinRNAs are packaged into extracellular vesicles released by infiltrating CD4T lymphocytes and subsequently delivered to β-cells during the early stages of autoimmune attack. Functional analyses revealed that overexpression of sinR-T has little effect on β-cell viability, whereas sinR-D markedly increases β-cell apoptosis. This finding suggests that the transfer of sinR-D contributes to β-cell destruction and the onset of type 1 diabetes. Furthermore, pull-down experiments with biotinylated sinRNAs identified Ago2, a core component of the RNA-induced silencing complex (RISC), as a binding partner of sinR-D, indicating mechanistic parallels with microRNA-mediated regulation. Collectively, our data uncover a novel role for sinRNAs as extracellularly transferred regulators of β-cell fate, expanding the repertoire of small RNAs implicated in the initiation of type 1 diabetes.