MicroRNA-29 specifies age-related differences in the CD8+ T cell immune response

MicroRNAs (miRNAs) have emerged as critical regulators of cell fate in the CD8+ T cell response to infection. Although there are several examples of miRNAs acting on effector CD8+ T cells after infection, it is unclear whether differential expression of one or more miRNAs in the naive state is consequential in altering their long-term trajectory. To answer this question, we examine the role of miR-29 in neonatal and adult CD8+ T cells, which express different amounts of miR-29 only prior to infection and adopt profoundly different fates after immune challenge. We find that manipulation of miR-29 expression in the naive state is sufficient for age-adjusting the phenotype and function of CD8+ T cells, including their regulatory landscapes and long-term differentiation trajectories after infection. Thus, miR-29 acts as a developmental switch by controlling the balance between a rapid effector response in neonates and the generation of long-lived memory in adults. [Display omitted] •miR-29 is required for the normal memory response of adult CD8+ T cells•miR-29 acts in naive cells to pre-program the immune response•Loss of miR-29 in adult cells impairs memory functions, mimicking neonatal cells•Gain of miR-29 in neonatal cells improves memory response Yee Mon et al. show that a small noncoding RNA, microRNA-29, specifies how CD8+ T cells, in humans and mice, will respond to infection even prior to encountering antigen. This pre-programing underlies the fundamental differences between adult and neonatal CD8+ T cells, which express miR-29 at different levels.