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
Affiliations
Marianne Dölz
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
Marko Hasiuk
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
John D. Gagnon
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
Mara Kornete
Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
Romina Marone
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
Glenn Bantug
Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
Robin Kageyama
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
Christoph Hess
Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Department of Medicine – CITIID, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK
K. Mark Ansel
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
Denis Seyres
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
Julien Roux
Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, Switzerland
Lukas T. Jeker
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; Corresponding author
Summary: 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.
