Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation
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The receptor programmed death 1 (PD-1) inhibits T cell proliferation and plays a critical role in suppressing self-reactive T cells, and it also compromises antiviral and antitumor responses. To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4(+) T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle. The ubiquitin ligase SCF(Skp2) degrades p27(kip1), an inhibitor of cyclin-dependent kinases (Cdks), and PD-1 blocked cell cycle progression through the G(1) phase by suppressing transcription of SKP2, which encodes a component of this ubiquitin ligase. Thus, in T cells stimulated through PD-1, Cdks were not activated, and two critical Cdk substrates were not phosphorylated. Activation of PD-1 inhibited phosphorylation of the retinoblastoma gene product, which suppressed expression of E2F target genes. PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G(1) phase inhibitor p15(INK4) and repressing the Cdk-activating phosphatase Cdc25A. PD-1 suppressed SKP2 transcription by inhibiting phosphoinositide 3-kinase-Akt and Ras-mitogen-activated and extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling. Exposure of cells to the proliferation-promoting cytokine interleukin-2 restored activation of MEK-ERK signaling, but not Akt signaling, and only partially restored SKP2 expression. Thus, PD-1 blocks cell cycle progression and proliferation of T lymphocytes by affecting multiple regulators of the cell cycle.
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Engagement of PD-1 causes tyrosine phosphorylation and an intracellular signaling cascade that mediates dephosphorylation of TCR proximal signaling components.
“In these cells, engagement of PD-1 causes tyrosine residues to become phosphorylated, starting an intracellular signaling cascade that mediates the dephosphorylation of TCR proximal signaling components (9, 42–44).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [42]
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- Authors
- Patsoukis, N., Brown, J., Petkova, V., Liu, F., Li, L., & Boussiotis, V. A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Patsoukis, Nikolaos
- Brown, Julia
- Boussiotis, Vassiliki A.
- Venue
- Science Signaling
- Published
- 2012-06-26
- Volume
- 5
- Issue
- 230
- Pages
- ra46-ra46
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC5498435
- OpenAlex
- W2144256523
- Cited by
- 529
- References
- 74
- Citations by year
- 2026: 19 · 2025: 38 · 2024: 34 · 2023: 51 · 2022: 49 · 2021: 67 · 2020: 62 · 2019: 48 · 2018: 40 · 2017: 43 · 2016: 18 · 2015: 22 · 2014: 16 · 2013: 14 · 2012: 6
- FWCI
- 7.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL107997-01, R21HL107997)
- National Institute of Allergy and Infectious Diseases (R56AI043552)
- 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 › Signaling Pathways in Disease
- Keywords
- PD-1, T cell proliferation, cell cycle regulation, G1 phase, p27, Skp2, cyclin-dependent kinases, retinoblastoma protein, E2F target genes, Smad3, CDC25A, Akt signaling, MEK/ERK signaling, interleukin-2, CD4+ T cells, immune checkpoint
- MeSH terms
- Humans, Interleukin-2, Phosphorylation, Transcription, Genetic, CD4-Positive T-Lymphocytes, Retinoblastoma Protein, G1 Phase, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, cdc25 Phosphatases, MAP Kinase Signaling System, S-Phase Kinase-Associated Proteins, Proto-Oncogene Proteins c-akt, Smad3 Protein, Cell Cycle Checkpoints, Programmed Cell Death 1 Receptor
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