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.
Highlights
The immune system must protect the organism against infectious diseases and cancer without provoking autoimmunity
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 T cell receptor (TCR) down-modulation
PD-L1 silencing in DCs inhibits CD8 TCR down-modulation In this study, we investigated the consequences and therapeutic outcomes of silencing the co-stimulatory ligand PD-L1 in DCs during antigen presentation to T cells
Summary
The immune system must protect the organism against infectious diseases and cancer without provoking autoimmunity. T lymphocytes play a key role in the induction of protective and long-lasting immunity, but, if uncontrolled, can cause autoreactive disease. For this reason, T cell activation is regulated at multiple levels, during antigen presentation. T cell activation is regulated at multiple levels, during antigen presentation Understanding these mechanisms is essential for designing effective therapies for the treatment of cancer, infectious diseases and autoimmune disorders. MHC-peptide recognition is not sufficient for full T cell activation, and a range of co-stimulatory ligand–receptor interactions is required that can provide either positive or negative signals. The overall integration of positive and negative signals during co-stimulation provides a checkpoint at which T cell responses are modulated (Nurieva et al, 2006)
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