Effects of PD-1 signaling on the molecular control of T cell expansion (178.17)

Abstract

Abstract Programmed death (PD)-1 is a potent T cell inhibitor critical for peripheral tolerance. Currently, it is unclear whether PD-1 has a global or a selective inhibitory effect on TCR signaling pathways involved in T cell expansion. It is also unclear how PD-1 affects the molecular machinery of cell cycle progression. Using primary human T cells we determined that PD-1 blocked cell cycle progression in the G1 phase. PD-1 did not alter the expression of G1 phase cyclins or cyclin-dependent kinases (Cdks) but, instead, suppressed transcription of the SCFSkp2 ubiquitin ligase that leads p27kip1 to degradation and resulted in accumulation of p27kip1. T cells receiving PD-1 signals displayed impaired Cdk2 activation and failed to phosphorylate Rb and Smad3 leading to suppression of E2F target genes but enhanced Smad3 transactivation. These events resulted in abrogation of the Cdk-activating phosphatase Cdc25A and upregulation of the Cdk4/6 inhibitor p15INK4. Suppression of Skp2 by PD-1 was mediated by inhibition of both PI3K/Akt and Ras/MEK/Erk pathways and was only partially reversed by IL-2, which restored activation of MEK/Erk but not Akt. In contrast to the inhibition of Ras and MEK/Erk pathway, PD-1 did not affect activation of Rap1, p38 and JNK MAP kinases. Thus, PD-1 selectively targets Ras/MEK/Erk and PI3K/Akt signaling to inhibit transcription of Skp2 and to activate Smad3 as an integral component of a pathway regulating blockade of cell cycle progression in T lymphocytes.