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

• Published in: Cell reports (Cambridge) Vol. 25; no. 8; pp. 2148 - 2162.e5
• Main Authors: Kim, Chulwoo, Hu, Bin, Jadhav, Rohit R., Jin, Jun, Zhang, Huimin, Cavanagh, Mary M., Akondy, Rama S., Ahmed, Rafi, Weyand, Cornelia M., Goronzy, Jörg J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-11-2018; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Aging - genetics; Aging - immunology; Apoptosis Regulatory Proteins - metabolism; Cell Differentiation - genetics; Gene Expression Regulation; HEK293 Cells; Humans; immune aging; Immunologic Memory - genetics; immunosenescence; Lymphocyte Activation - genetics; MAP Kinase Signaling System; Membrane Proteins - metabolism; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Phosphoproteins - metabolism; PTEN Phosphohydrolase - metabolism; RNA-Binding Proteins - metabolism; short-lived T effector cell; T cell differentiation; T memory cell; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; TOR Serine-Threonine Kinases - metabolism; Transcription Factor AP-1 - metabolism; vaccination; Young Adult; T memory cell; immunosenescence; T cell differentiation; short-lived T effector cell; microRNA; immune aging; vaccination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.10.074

Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies 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 transcriptome 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 pathways 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.
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•Upregulation of miR-21 upon T cell activation promotes effector cell differentiation•Expression of miR-21 in naive CD4 T cells increases with age•T cell responses in old individuals favor effector over memory cell differentiation•miR-21 attenuation induces transcription factor networks supportive of memory cells
A hallmark of the aging immune system is its failure to induce long-lived memory. Kim et al. report that increased expression of miR-21 in naive T cells from older individuals sustains signaling in the MAPK and AKT-mTORC pathways, disfavoring induction of transcription factor networks involved in memory cell generation.