MicroRNA-29a enhances and preserves stem-like CD8 T cell differentiation by regulating master epigenetic circuits of...

CD8 T cells mediate protective immune responses. However, persisting antigens such as chronic viruses or tumors redirect CD8 T cell differentiation to a sub-optimal, epigenetically defined state called exhaustion. Exhausted T cells (T_EX) lose their ability to persist long-term and to initiate functional memory responses. Checkpoint inhibitor blockade temporarily restores effector functions, but immune reinvigoration is not long-lasting, due to the epigenetic stability of T_EX. Therefore, epigenetic reprogramming of T_EX leading to durable T cell responses is essential to improve disease control. Here, we demonstrate that a single microRNA (miR), miR-29a, epigenetically re-directs T_EX differentiation and preserves T_EX into a stem-like state, leading to long-term persisting progenitor T_EX. MiR-29a rewires epigenetic maintenance programs, including downregulation of key exhaustion-associated regulators (Dnmt1, Dnmt3a, and Dnmt3b), alongside increased expression of progenitor- and stemness-associated genes such as Tcf7 and Il7r. These reprogrammed CD8 T cells are more sensitive to PD-L1 checkpoint blockade. Ectopic expression of miR-29a combined with aPD-L1 treatments enhances effector responses, while preserving T cell stemness. Together, our findings suggest that miR-29a can be leveraged to overcome current barriers to immune checkpoint blockade.