Functional pathways regulated by microRNA networks in CD8 T‐cell aging

One of the most prominent immunological changes during human aging is the alteration in CD8 T‐cell subset distribution, predominated by a loss of naïve CD8 T cells. The molecular mechanisms that contribute to the loss of naïve CD8 T‐cells during aging remain unclear. Considering that many CD8 T‐cell functions are influenced by microRNAs (miRNAs), we explored miRNA expression profiling to identify novel dysfunctions that contribute to naïve CD8 T‐cell loss during aging. Here, we describe age‐dependent miRNA expression changes in naïve, central memory, and effector memory CD8 T‐cell subsets. Changes in old naïve CD8 T‐cells partially resembled those driven by an underlying shift in cellular differentiation toward a young central memory phenotype. Pathways enriched for targets of age‐dependent miRNAs included FOXO1, NF‐κB, and PI3K‐AKT signaling. Transcriptome analysis of old naïve CD8 T‐cells yielded corresponding patterns that correlated to those seen with reduced FOXO1 or altered NF‐κB activities. Of particular interest, IL‐7R expression, controlled by FOXO1 signaling, declines on naïve CD8 T cells with age and directly correlates with the frequencies of naïve CD8 T cells. Thus, age‐associated changes in miRNA networks may ultimately contribute to the failure in CD8 T‐cell homeostasis exemplified by the loss in naïve cells.