MicroRNA-29a attenuates exhaustion and promotes memory-like CD8 T cells

Abstract CD8 T cells are crucial for immunity against pathogens and tumor cells. However, persistent antigens during chronic infections and cancers drive the differentiation of exhausted T cells (TEX). TEX do not generate optimal immune responses to persistent antigens. The epigenetic profile of TEX is altered and cannot be reversed with current immunotherapy, such as PD-L1 blockade, providing a challenge for the efficacy of such therapies. Despite considerable work interrogating the transcriptional regulation of TEX, the post-transcriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses, attenuated exhaustion, and fostered a memory-like CD8 T cell differentiation state during chronic infection. Importantly, miR-29a combined with anti-PD-L1 therapy increased CD8 T cell accumulation, promoted a progenitor-like TEX subset and enhanced a memory-like phenotype long-term. These data indicate that miR-29a can instruct CD8 T cell differentiation and promote memory-like responses. Therefore, we suggest miR-29a as a novel immunotherapeutic to regulate TEX differentiation and promote functional CD8 T cell responses long-term.