Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Abstract

SUMMARY Induction of protective vaccine responses, governed by the successful generation of antigen-specific anti-bodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcrip-tome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling path-ways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses.

Cellular senescence contributes to age‐dependent changes in circulating extracellular vesicle cargo and function

“…The importance of our findings is twofold. First, our data suggest that changes in EV-like particle miRNA levels can be moni- Elevated miR-21 can also induce senescence and reduce angiogenic potential in endothelial cells (Dellago et al, 2013) as well as impair T-cell activation (Kim et al, 2018). Changes in miR-223 and let-7a…”

Immune cell repertoires in breast cancer patients after adjuvant chemotherapy

“…CD4 + T cell responses to newly encountered viruses such as West Nile or Zika virus may also be impaired, due the contraction of the naive compartment. The shift in CD4 + Tem composition toward more inflammatory populations should exacerbate a trend that is generally seen with normal aging (51,52) and could contribute to accelerated inflammaging. In addition, this inflammatory bias can impair the generation of T follicular cells in favor of effector cells (52) and, therefore, reduce the induction of effective B cell memory responses.…”

“…The shift in CD4 + Tem composition toward more inflammatory populations should exacerbate a trend that is generally seen with normal aging (51,52) and could contribute to accelerated inflammaging. In addition, this inflammatory bias can impair the generation of T follicular cells in favor of effector cells (52) and, therefore, reduce the induction of effective B cell memory responses. Similarly, the decline in memory B cells we observed is short-term but severe, and it is highly likely that the regenerated B cell receptor repertoire is not sufficiently protective.…”

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

“…Naïve human T cells exhibit phenotypic changes that are suggestive for partial activation or differentiation (den Braber et al, ; Kohler & Thiel, ; Pekalski et al, ). Also, alterations in microRNA expression patterns with aging are indicative of T‐cell differentiation, including the loss of miR‐181a (Gustafson et al, ; Li et al, ) and an increase in miR‐21 that favors the activation of TF networks characterized by the reduction in TCF7, BCL6, and ID3 (Kim et al, ). Finally, our studies on the epigenome of human naïve CD8 T cells have shown an aging‐associated increased accessibility for bZIP family TFs, including BATF, which is reminiscent of effector cells (Moskowitz et al, ).…”