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 naive CD8 T cells. The molecular mechanisms that contribute to the loss of naive 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 naive CD8 T-cell loss during aging. Here, we describe age-dependent miRNA expression changes in naive, central memory, and effector memory CD8 T-cell subsets. Changes in old naive 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-B, and PI3K-AKT signaling. Transcriptome analysis of old naive CD8 T-cells yielded corresponding patterns that correlated to those seen with reduced FOXO1 or altered NF-B activities. Of particular interest, IL-7R expression, controlled by FOXO1 signaling, declines on naive CD8 T cells with age and directly correlates with the frequencies of naive 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 naive cells.