文章基本信息

标题：Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4 + T cells
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作者：Marianne Dölz ; Marko Hasiuk ; John D. Gagnon 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：11
页码：1-31
DOI：10.1016/j.isci.2022.105372
语种：English
出版社：Elsevier
摘要：SummaryCD28 provides the prototypical costimulatory signal required for productive T-cell activation. Known molecular consequences of CD28 costimulation are mostly based on studies of protein signaling molecules. The microRNA cluster miR-17∼92 is induced by T cell receptor stimulation and further enhanced by combined CD28 costimulation. We demonstrate that transgenic miR-17∼92 cell-intrinsically largely overcomes defects caused by CD28 deficiency. Combining genetics, transcriptomics, bioinformatics, and biochemical miRNA:mRNA interaction maps we empirically validate miR-17∼92 target genes that include several negative regulators of T cell activation. CD28-deficient T cells exhibit derepressed miR-17∼92 target genes during activation. CRISPR/Cas9-mediated ablation of the miR-17∼92 targetsPtenandNrbp1in naive CD28−/−CD4+T cells differentially increases proliferation and expression of the activation markers CD25 and CD44, respectively. Thus, we propose that miR-17∼92 constitutes a central mediator for T cell activation, integrating signals by the TCR and CD28 costimulation by dampening multiple brakes that prevent T cell activation.Graphical abstractDisplay OmittedHighlights•Empirically validated direct miR-17∼92 target gene list in mouse CD4+T cells•CD28-deficient CD4+T cells exhibit derepressed miR-17∼92 targets during activation•Transgenic miR-17∼92 expression rescues CD28-deficiencyin vitroandin vivo•miR-17∼92 target KO in naive CD28-deficient CD4+T cells restores distinct phenotypesBiological sciences; Molecular mechanism of gene regulation; Immunology