Forced expression of the non-coding RNA miR-17â¼92 restores activation and function in CD28-deficient CD4+ T cells.
iScience
; 25(11): 105372, 2022 Nov 18.
Article
en En
| MEDLINE
| ID: mdl-36388982
ABSTRACT
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-17â¼92 is induced by T cell receptor stimulation and further enhanced by combined CD28 costimulation. We demonstrate that transgenic miR-17â¼92 cell-intrinsically largely overcomes defects caused by CD28 deficiency. Combining genetics, transcriptomics, bioinformatics, and biochemical miRNAmRNA interaction maps we empirically validate miR-17â¼92 target genes that include several negative regulators of T cell activation. CD28-deficient T cells exhibit derepressed miR-17â¼92 target genes during activation. CRISPR/Cas9-mediated ablation of the miR-17â¼92 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-17â¼92 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Idioma:
En
Revista:
IScience
Año:
2022
Tipo del documento:
Article
País de afiliación:
Suiza