Karwacz, KatarzynaBricogne, ChristopherMacDonald, DouglasArce, FrederickBennett, Clare L.Collins, MaryEscors, David2013-01-032011Karwacz, Katarzyna, Christopher Bricogne, Douglas MacDonald, Frederick Arce, Clare L. Bennett, Mary Collins, and David Escors. 2011. PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on \(CD8^+\) T cells. EMBO Molecular Medicine 3(10): 581-592.1757-4676http://nrs.harvard.edu/urn-3:HUL.InstRepos:10125929T 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.en-USJournal Article2013-01-0310.1002/emmm.201100165