Dölz Marianne, Hasiuk Marko, Gagnon John D, Kornete Mara, Marone Romina, Bantug Glenn, Kageyama Robin, Hess Christoph, Ansel K Mark, Seyres Denis, Roux Julien, Jeker Lukas T
Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.
iScience. 2022 Oct 17;25(11):105372. doi: 10.1016/j.isci.2022.105372. eCollection 2022 Nov 18.
CD28 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 targets and in 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.
CD28为有效的T细胞活化提供了典型的共刺激信号。已知的CD28共刺激的分子后果大多基于对蛋白质信号分子的研究。微小RNA簇miR-17∼92由T细胞受体刺激诱导，并通过联合CD28共刺激进一步增强。我们证明，转基因miR-17∼92在细胞内在水平上很大程度上克服了由CD28缺陷引起的缺陷。结合遗传学、转录组学、生物信息学和生化miRNA:mRNA相互作用图谱，我们通过实验验证了miR-17∼92的靶基因，其中包括几个T细胞活化的负调节因子。CD28缺陷的T细胞在活化过程中表现出miR-17∼92靶基因的去抑制。CRISPR/Cas9介导的miR-17∼92靶基因在初始CD28缺陷的CD4 T细胞中的缺失分别差异性地增加了增殖以及活化标志物CD25和CD44的表达。因此，我们提出miR-17∼92构成T细胞活化的核心介质，通过减弱多个阻止T细胞活化的制动机制来整合TCR和CD28共刺激的信号。
