| First Author | Dölz M | Year | 2022 |
| Journal | iScience | Volume | 25 |
| Issue | 11 | Pages | 105372 |
| PubMed ID | 36388982 | Mgi Jnum | J:337608 |
| Mgi Id | MGI:7386502 | Doi | 10.1016/j.isci.2022.105372 |
| Citation | Dolz M, et al. (2022) Forced expression of the non-coding RNA miR-17 approximately 92 restores activation and function in CD28-deficient CD4(+) T cells. iScience 25(11):105372 |
| abstractText | 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 approximately 92 is induced by T cell receptor stimulation and further enhanced by combined CD28 costimulation. We demonstrate that transgenic miR-17 approximately 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 approximately 92 target genes that include several negative regulators of T cell activation. CD28-deficient T cells exhibit derepressed miR-17 approximately 92 target genes during activation. CRISPR/Cas9-mediated ablation of the miR-17 approximately 92 targets Pten and Nrbp1 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 approximately 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. |
