• Open Access

PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells

Authors

  • Katarzyna Karwacz,

    1. Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London, UK
    2. Center for Neurologic Disease, Harvard Medical School, Boston, MA, USA
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    • These authors contributed equally to this work.

  • Christopher Bricogne,

    1. Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London, UK
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    • These authors contributed equally to this work.

  • Douglas MacDonald,

    1. Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London, UK
    2. UCL Cancer Institute, University College London, London, UK
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  • Frederick Arce,

    1. Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London, UK
    2. UCL Cancer Institute, University College London, London, UK
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  • Clare L. Bennett,

    1. Division of Cancer Studies, Royal Free Campus, University College London, London, UK
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  • Mary Collins,

    1. Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London, UK
    2. UCL Cancer Institute, University College London, London, UK
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    • These authors contributed equally to this work.

  • David Escors

    Corresponding author
    1. Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London, UK
    2. Rayne Institute, University College London, London, UK
    • Tel: +44 2031082175; Fax: +44 2076797920
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    • These authors contributed equally to this work.


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.

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