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.