Immunity & infection
Neonates are highly susceptible to infection and respond poorly to vaccination for reasons that are not well understood. Based on our published data, we believe neonates are particularly vulnerable to repeated infections because their naïve CD8+ T cells are intrinsically defective at differentiating into memory CD8+ T cells. To understand the underlying basis for these age-related differences, we performed smallRNA sequencing and found that one miRNA particularly (miR-29) was selectively upregulated in adult CD8+ T cells (mice and humans) and acting on their target genes in a predictable manner. We also performed adoptive transfer experiments and compared the ability of WT and miR29KO donor CD8+ T cells to respond to infection. Interestingly, we found that donor mir29KO CD8+ T cells secreted more effector molecules (IFNg, gzmB), expressed higher levels of transcription factors (Tbet, Eomes) associated with effector cell differentiation, and failed to form certain subsets of memory CD8+ T cells (central memory, tissue resident memory), similar to neonatal CD8+ T cells. To translate these findings to humans, we manipulated mir-29 expression in naïve human CD8+ T cells. By introducing mir-29 mimics and antagomirs, we were able to age-adjust mir-29 expression and target genes in neonatal (cord) and adult CD8+ T cells (PBMCs) and are currently comparing the ability of these cells to respond to stimulation. Our research on miR-29 has the potential to uncover novel therapeutic strategies for enhancing the development of neonatal memory CD8+ T cells and identify biomarkers for predicting how individuals respond to vaccination.