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. We demonstrate a novel mechanism whereby 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 triggers ligand-induced TCR down-modulation. This occurred via Cbl-b E3 up-regulation in CD8 T cells. PD-L1 silencing in DCs with lentiviral vectors delivering microRNAs markedly inhibited TCR down-modulation. PD-L1 silencing hyper-activated CD8 T cells as assessed in vitro and in vivo in an arthritis model. Antitumour immune responses (lymphoma and melanoma) were accelerated and DC anti-tumour capacities potentiated, when combined with mitogen-activated kinase (MAPK) modulators that promote DC activation, or with cytokine priming.
|Journal||Human Gene Therapy|
|Publication status||Published - 1 Dec 2013|
|Event||The European Society for Gene and Cell Therapy and the Spanish Society for Gene and Cell Therapy Collaborative Congress 2013 - Madrid, Spain|
Duration: 25 Oct 2013 → 28 Oct 2013
- T cell