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Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell
Nikolaos Patsoukis1, Julia Brown, Victoria Petkova
1Department of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
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.
Insights
Programmed death 1 (PD-1) inhibits T cell proliferation by blocking cell cycle progression. PD-1 signaling suppresses SKP2 transcription, impacting cyclin-dependent kinases and leading to T cell cycle arrest.
Area of Science:
- Immunology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Programmed death 1 (PD-1) is a receptor that inhibits T cell proliferation and immune responses.
- Understanding the molecular mechanisms by which PD-1 suppresses T cell activity is crucial for developing immunotherapies.
Purpose of the Study:
- To investigate how PD-1 signaling impacts the molecular control of the cell cycle in human CD4(+) T cells.
- To elucidate the specific pathways and regulators affected by PD-1 in T cell proliferation.
Main Methods:
- Utilized human CD4(+) T cells to examine PD-1 signaling effects on cell cycle regulators.
- Analyzed the transcription of SKP2, a key ubiquitin ligase component, and its downstream effects.
- Investigated the phosphorylation status of Cdk substrates, including the retinoblastoma gene product and Smad3.
- Assessed the impact on cell cycle inhibitors (p15(INK4)) and activators (Cdc25A).
- Examined the role of phosphoinositide 3-kinase-Akt and MEK-ERK signaling pathways.
Main Results:
- PD-1 signaling suppressed SKP2 transcription, leading to decreased degradation of the Cdk inhibitor p27(kip1).
- This suppression resulted in inhibited Cdk activation and phosphorylation of critical Cdk substrates.
- PD-1 activation led to inhibited phosphorylation of the retinoblastoma gene product, suppressing E2F target genes.
- PD-1 also inhibited Smad3 phosphorylation, increasing its activity and inducing cell cycle arrest.
- PD-1 increased p15(INK4) abundance and repressed Cdc25A, reinforcing G(1) phase inhibition.
- PD-1 suppressed SKP2 transcription by inhibiting Akt and MEK-ERK signaling pathways.
Conclusions:
- PD-1 blocks T cell cycle progression at the G(1) phase by suppressing SKP2 transcription.
- PD-1 signaling impacts multiple cell cycle regulators, including Cdks, p27(kip1), retinoblastoma protein, Smad3, p15(INK4), and Cdc25A.
- The findings reveal a complex molecular network through which PD-1 inhibits T lymphocyte proliferation, offering potential targets for immune modulation.
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