Limited roles of the miR-17-92 cluster in the regulation of T-cell apoptosis

Abstract

The pro-apoptotic BCL-2-interacting mediator of cell death [BIM; also known as Bcl-2-like protein 11 (BCL2L11)] is a crucial regulator of programmed cell death in immune cells, with roles in T-cell development, homeostasis, and immune response modulation. However, the precise molecular mechanisms that regulate BIM expression in these processes are not completely understood. One possible regulatory mechanism involves microRNAs, small noncoding RNAs that silence target messenger RNAs (mRNAs). The miR-17-92 cluster, which has been implicated in immune regulation, has nine predicted binding sites in the 3' untranslated region of the Bcl2l11 mRNA (thereafter referred to as Bim mRNA). To explore whether direct miR-17-92-mediated regulation of BIM controls apoptosis in T cells, a genetically modified mouse model with disrupted miR-17-92:Bim interactions specifically in T cells has been used. The results revealed that loss of miR-17-92:Bim binding, although leading to a modest increase of BIM protein in double-positive (DP) thymocytes and naïve CD8⁺ T cells, does not measurably affect early T-cell development or peripheral T-cell numbers. However, the absence of this interaction led to a moderate reduction in Th₁₇ CD4⁺ T cells at a steady state. Collectively, these findings suggest that miR-17-92-mediated regulation of BIM does not play major roles in T-cell apoptosis and homeostasis, highlighting the existence of alternative regulatory mechanisms controlling BIM pro-apoptotic activity.

Keywords: BIM; T cells; apoptosis; miR‐17‐92.