The non-coding RNA miR-17~92 is a central mediator of T cell activation

Abstract

T cell activation is paramount for productive adaptive immune responses. CD28 is a key clinically targeted immunoregulatory receptor because it provides the prototypical costimulatory signal required for T cell activation. Therefore, a precise understanding of the molecular consequences of CD28 costimulation has direct therapeutic relevance. Here, we uncover that the microRNA cluster miR-17∼92 is part of the molecular program triggered by CD28 costimulation and hence T cell activation. Combining genetics, transcriptomics, bioinformatics and biochemical miRNA:mRNA interaction maps we demonstrate that transgenic miR-17∼92 can cell-intrinsically largely overcome defects caused by CD28-deficiency. miR-17∼92 promotes transcription of a proinflammatory gene signature by enhancing the calcineurin/NFAT pathway. miR-17∼92 binds to and represses a network of genes including several negative regulators of T cell activation. Finally, CD28-deficient T cells exhibit derepressed miR-17∼92 target genes during activation, demonstrating that this non-coding RNA is required to shape the transcriptome. Thus, we propose that miR-17∼92 constitutes a central mediator for T cell activation, integrating signals by the TCR and CD28 costimulation. In this model miR-17∼92 facilitates T cell activation by dampening the breaks that prevent T cell activation.

Sequence determinants as key regulators in gene expression of T cells

“…mRNAs that use codons for highly abundant tRNA (green) will translate faster than those with codons for low abundance tRNA (yellow), which in turn affects protein and mRNA levels Phlpp2, Cyld, and Rcan3, which results in increased calcineurin/NFAT signaling. 52 The importance of miRNAs in T cell development and differentiation is exemplified by the severely impaired development and differentiation of T cells in mice that are devoid of the miRNA processing ribonuclease Dicer, which impairs the overall miRNA expression. 53,54 Recent studies also highlight the role of individual miRNAs.…”

“… 51 The miR‐17 ~ 92 cluster also plays an important role in T cell activation by repressing negative regulators of T cell activation, including Phlpp2 , Cyld, and Rcan3 , which results in increased calcineurin/NFAT signaling. 52 …”

TGF-β specifies T FH versus T H 17 cell fates in murine CD4 + T cells through c-Maf

“…datacurators.nl/tide/) (89). Cas9 ribonucleoproteins (RNPs) were prepared according to previously described protocols (90)(91)(92). CRISPR RNA (crRNA) and trans-activating RNA (tracrRNA; #1072534) (both IDT) were mixed in equimolar concentrations in a sterile microcentrifuge tube or polymerase chain reaction plate, incubated at 95°C for 5 min, and cooled down at room temperature for 10 min.…”