title: Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation.
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.
authors: Department of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Nikolaos
authors: N
authors: Patsoukis
authors: Julia
authors: J
authors: Brown
authors: Victoria
authors: V
authors: Petkova
authors: Fang
authors: F
authors: Liu
authors: Lequn
authors: L
authors: Li
authors: Vassiliki A
authors: VA
authors: Boussiotis
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C508594:IL2 protein, human; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D051057:Proto-Oncogene Proteins c-akt; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D018631:ras Proteins