title: PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells.
abstract: 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.
authors: Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, UK.
authors: Katarzyna
authors: K
authors: Karwacz
authors: Christopher
authors: C
authors: Bricogne
authors: Douglas
authors: D
authors: MacDonald
authors: Frederick
authors: F
authors: Arce
authors: Clare L
authors: CL
authors: Bennett
authors: Mary
authors: M
authors: Collins
authors: David
authors: D
authors: Escors
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000473:pathology; D016086:Lentivirus / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology; D034741:RNA, Small Interfering / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014611:Vaccination
chemical_list: D060890:B7-H1 Antigen; D008024:Ligands; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D044767:Ubiquitin-Protein Ligases