期刊
EMBO MOLECULAR MEDICINE
卷 3, 期 10, 页码 581-592出版社
WILEY
DOI: 10.1002/emmm.201100165
关键词
Cbl; dendritic cells; PD-1; PD-L1; TCR
资金
- Medical Research Council UK
- University College London Hospitals/University College London Comprehensive Biomedical Research Centre
- Arthritis Research UK [18433]
- Medical Research Council [G0900374, G9721629, G0900950, G0900950B, G9721629B] Funding Source: researchfish
- Versus Arthritis [18433] Funding Source: researchfish
- MRC [G0900950, G0900374, G9721629] Funding Source: UKRI
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.
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