Signaling via PD-1 controls the expression of cyclins and the activation of cdk2 in human primary CD4+ T cells (50.30)

Abstract

Abstract The Programmed Death 1 (PD-1) pathway plays a critical role in the inhibition of T cell activation and the maintenance of T cell tolerance. Expressed by activated T cells, PD-1 downregulates T cell effector function upon engagement with its ligands PD-L1 and PD-L2. Although vital for the inhibition of self-directed immune responses in several models of autoimmunity, expression of PD-L1 and PD-L2 by malignant tissues can prevent effective tumor-specific immunity. Furthermore, the ligation of PD-1 results in T cell exhaustion in several chronic viral infections. PD-1 mediated signaling via SHP-2 decreases Akt activation via inhibition of PI3K, but little is known about mechanisms of cell cycle regulation. Using anti-CD3 with or without anti-PD-1 conjugated to magnetic beads plus soluble anti-CD28, we have examined the expression of cell cycle mediators upon stimulation of human primary CD4+ T cells. Analysis of cell lysates by western blot revealed that signaling via PD-1 inhibited the upregulation of Skp2 and prevented the degradation of p27kip1 and the expression of cyclin E and cyclin A. Furthermore, despite abundant levels of cdk2, ligation of PD-1 prevented cdk2 phosphorylation on Thr 160 thereby inhibiting the G1/S phase transition and progression through S phase. We conclude that inhibition of T cell activation via PD-1 signaling has direct consequences for the expression and regulation of integral proteins involved in the cell cycle.