期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 52, 页码 18036-18050出版社
ELSEVIER
DOI: 10.1074/jbc.RA120.014745
关键词
T cell; programmed cell death protein 1 (PD-1); programmed cell death ligand 2 (PD-L2); phosphoproteomics; cell signaling; mass spectrometry; signaling networks; immunology; T cell receptor (TCR); inhibition mechanism; immunotherapy; kinase-substrate relationships
资金
- NIAID, National Institutes of Health [AI125640]
- National Institutes of Health [CA231277]
- Cancer Research Institute
- Eppley Foundation for Research
Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell-mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell-mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1-triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1-targeting therapeutic approaches.
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