Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2
Open accessAbstract
Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.
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Ligation of PD-1 with its ligands PD-L1 or PD-L2 induces tyrosine phosphorylation of the PD-1 cytoplasmic domain by phosphorylating kinase Lck and subsequent recruitment of cytosolic tyrosine phosphatase SHP-2 and PD-1-associated SHP-2 preferentially dephosphorylates CD28 and suppresses CD28 costimulatory signaling leading to restrained effector T cell function.
“Ligation of PD-1 with its ligands programmed death-ligand 1 or 2 (PD-L1 or PD-L2) induces tyrosine phosphorylation of the PD-1 cytoplasmic domain by phosphorylating kinase Lck and subsequent recruitment of cytosolic tyrosine phosphatase SHP-2 and PD-1-associated SHP-2 preferentially dephosphorylates CD28 and suppresses CD28 costimulatory signaling leading to restrained effector T cell function (49”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [50]
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Experimental — accuracy not yet measuredSHP2 has effects on parallel pathways (e.g., JAK/STAT signaling) and is implicated as an effector of inhibitory signaling by PD-1 and some other immune checkpoint receptors.
“SHP2 also has effects on parallel pathways (e.g., JAK/STAT signaling) and is implicated as an effector of inhibitory signaling by PD-1 and some other immune checkpoint receptors (Hui et al., 2017; Peled et al., 2018; Yokosuka et al., 2012).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Yokosuka et al., 2012
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- Authors
- Yokosuka, T., Takamatsu, M., Kobayashi-Imanishi, W., Hashimoto-Tane, A., Azuma, M., & Saito, T.
- Affiliations
- Japan Science and Technology Agency (JP)
- RIKEN (JP)
- Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan 1
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Yokosuka, Tadashi
- Saito, Takashi
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2012-05-28
- Volume
- 209
- Issue
- 6
- Pages
- 1201-1217
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3371732
- OpenAlex
- W2107556275
- Cited by
- 1,161
- References
- 51
- Citations by year
- 2026: 77 · 2025: 87 · 2024: 121 · 2023: 116 · 2022: 127 · 2021: 129 · 2020: 106 · 2019: 95 · 2018: 63 · 2017: 73 · 2016: 52 · 2015: 40 · 2014: 29 · 2013: 36 · 2012: 9
- FWCI
- 15.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (23249082, 24590590, 24229004, 24590591)
- Japan Science and Technology Agency
- Precursory Research for Embryonic Science and Technology
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- PD-1, T cell receptor signaling, SHP2, PD-L1, T cell activation suppression, PD-L1 inhibitors, single-cell imaging, T cell exhaustion
- MeSH terms
- Amino Acid Sequence, Animals, Lymphocyte Activation, Mice, Mutant Strains, Molecular Sequence Data, Phosphorylation, Receptors, Antigen, T-Cell, T-Lymphocytes, Tyrosine, Signal Transduction, CD8-Positive T-Lymphocytes, Amino Acid Motifs, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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