miR29 imposes quiescence in mature B cells by repressing the SP1/MYC/miR17-92 activation circuit

Cellular quiescence is a defining feature of mature immune cells, balancing long-term survival with the capacity for rapid activation while preserving tissue homeostasis. Despite its importance, the molecular mechanisms enforcing quiescence remain incompletely understood. In the B lineage, regulation of the PTEN/PI3K signaling axis is critical for the survival of quiescent cells. We previously demonstrated that miR29 replaces miR17-92 in controlling PTEN/PI3K signaling during B-cell maturation. Here, we show that miR29 expression in mature B cells is essential for imposing and maintenance of their quiescence stage. Using a miR29 targeting antagomiR and conditional ablation of miR29 in CD23-expressing B cells, we show that repression of miR29 in mature quiescent B cells enhances PI3K signaling and induces miR17-92 expression. This regulatory switch promotes increased survival and exit from cellular quiescence. Mechanistically, we found that miR29 represses SP1 in quiescent B cells, thereby limiting MYC expression and the downstream induction of miR17-92. Together, our results suggest that miR29 imposes cellular quiescence in mature B cells by repressing the SP1/MYC/miR17-92 activating axis, illustrating how dynamic microRNA networks remodel intracellular programs to control cellular states.