Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4+ T cells

Marianne Dölz; Marko Hasiuk; John D Gagnon; Mara Kornete; Romina Marone; Glenn Bantug; Robin Kageyama; Christoph Hess; K Mark Ansel; Denis Seyres; Julien Roux; Lukas T Jeker

doi:10.1016/j.isci.2022.105372

Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4⁺ T cells

iScience. 2022 Oct 17;25(11):105372. doi: 10.1016/j.isci.2022.105372. eCollection 2022 Nov 18.

Authors

Marianne Dölz^{1

2}, Marko Hasiuk^{1

2}, John D Gagnon^{3

4}, Mara Kornete¹, Romina Marone^{1

2}, Glenn Bantug¹, Robin Kageyama^{3

4}, Christoph Hess^{1

5}, K Mark Ansel^{3

4}, Denis Seyres^{1

2}, Julien Roux^{1

6}, Lukas T Jeker^{1

2}

Affiliations

¹ Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
² Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.
³ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Medicine - CITIID, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
⁶ Swiss Institute of Bioinformatics, Basel, Switzerland.

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-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 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∼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.

Keywords: Biological sciences; immunology; molecular mechanism of gene regulation.

Abstract

Grants and funding