MicroRNA-29a attenuates CD8 T cell exhaustion and induces memory-like CD8 T cells during chronic infection

CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality and reduced protective capacity. 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 during chronic viral infection and antagonized exhaustion. CD45.1+ P14 CD8 T cells were transduced with either control-VEX retrovirus or miR-29a overexpressing-VEX retrovirus and adoptively transferred to CD45.2+ recipient mice that were infected with LCMV clone 13 at 24 hrs earlier. At d30 p.i., VEX+ and VEX- P14 cells were sorted and RNASeq was performed. MiR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and TCR signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion towards a more beneficial memory-like CD8 T cell differentiation state.