PD-1 protects expanding human T cells from premature restimulation-induced cell death by modulating TCR and CD28 signaling.

Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on T cells that dampens TCR and CD28 signaling in the immunological synapse. PD-1 is significantly upregulated on T cells in the tumor microenvironment, where it promotes exhaustion in the context of chronic antigen restimulation. Exhaustion renders T cells hyporesponsive and ineffectual, but potentially resistant to restimulation-induced cell death (RICD). Restimulation-induced cell death (RICD) is a critical propriocidal apoptosis program triggered in activated T cells upon robust TCR re-engagement, which serves to constrain effector T cell expansion and longevity to prevent collateral tissue damage. While the checkpoint function of PD-1 has profound implications for cancer immunotherapy, the role of PD-1 in regulating newly activated T cells remains unclear. We hypothesized that PD-1 attenuates RICD sensitivity in human effector T cells by modulating TCR signal strength. Here we show that transient upregulation of PD-1 helps to protect clonally expanding human CD4+ and CD8 + T cells from premature RICD, with only moderate protection noted in terminally-differentiated, PD-1