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

• Type of Material: Article
• 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
• Language: English
• Date: 2018-11-20
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2018.10.074
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 25
• Issue: 8
• Start Page: 2148
• End Page: +
• Grant/Funding Information: This work was supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, and P01 HL129941 to C.M.W. and R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191, and I01 BX001669 to J.J.G.).
• Keywords: MIR-181A; SURVIVAL; MICRORNA REGULATION; EXPRESSION; DIFFERENTIATION; Science & Technology; Life Sciences & Biomedicine; Cell Biology; IMPAIRS; SENSITIVITY; EFFECTOR; SUPPRESSOR PDCD4; EFFICACY
• Research Categories: Biology, Cell

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.