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

• Authors: Chulwoo Kim, Stanford University; Bin Hu, Stanford University; Rohit R. Jadhav, Stanford University; Jun Jin, Stanford University; Huimin Zhang, Stanford University; Mary M. Cavanagh, Stanford University; Rama Akondy, Emory University; Rafi Ahmed, Emory University; Cornelia M. Weyand, Stanford University; Jorg J. Goronzy, Stanford University
• Journal Title: Cell Reports
• Volume: Volume 25, Number 8
• Publisher: Elsevier (Cell Press): OAJ | 2018-11-20, Pages 2148-+
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.celrep.2018.10.074
• Subjects: Biology, Cell
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; MICRORNA REGULATION; SUPPRESSOR PDCD4; EXPRESSION; EFFECTOR; DIFFERENTIATION; SENSITIVITY; SURVIVAL; EFFICACY; MIR-181A; IMPAIRS

Abstract

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-21 high 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. 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.