These authors contributed equally to this work.
PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells
Article first published online: 10 AUG 2011
Copyright © 2011 EMBO Molecular Medicine
EMBO Molecular Medicine
Volume 3, Issue 10, pages 581–592, October 2011
How to Cite
Karwacz, K., Bricogne, C., MacDonald, D., Arce, F., Bennett, C. L., Collins, M. and Escors, D. (2011), PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells. EMBO Mol Med, 3: 581–592. doi: 10.1002/emmm.201100165
- Issue published online: 10 OCT 2011
- Article first published online: 10 AUG 2011
- Accepted manuscript online: 8 JUL 2011 05:10AM EST
- Manuscript Accepted: 1 JUL 2011
- Manuscript Revised: 28 JUN 2011
- Manuscript Received: 5 MAY 2011
- dendritic cells;
T cell receptor (TCR) down-modulation after antigen presentation is a fundamental process that regulates TCR signal transduction. Current understanding of this process is that intrinsic TCR/CD28 signal transduction leads to TCR down-modulation. Here, we show that the interaction between programmed cell death 1 ligand 1 (PD-L1) on dendritic cells (DCs) and programmed death 1 (PD-1) on CD8 T cells contributes to ligand-induced TCR down-modulation. We provide evidence that this occurs via Casitas B-lymphoma (Cbl)-b E3 ubiquitin ligase up-regulation in CD8 T cells. Interference with PD-L1/PD-1 signalling markedly inhibits TCR down-modulation leading to hyper-activated, proliferative CD8 T cells as assessed in vitro and in vivo in an arthritis model. PD-L1 silencing accelerates anti-tumour immune responses and strongly potentiates DC anti-tumour capacities, when combined with mitogen-activated kinase (MAPK) modulators that promote DC activation.