PD-1 protects expanding human T cells from premature restimulation-induced cell death.

Abstract

Abstract Programmed cell death-1 (PD-1) is a co-inhibitory protein that dampens TCR/CD28 signaling in part by recruiting the phosphatase SHP2 to the immunological synapse. Chronic antigenic restimulation of T cells can induce apoptosis or elicit PD-1-mediated exhaustion, rendering them hyporesponsive and ineffectual. While the checkpoint function of PD-1 has profound implications for cancer immunotherapy, the role of PD-1 in conventional effector T cell responses remains unclear. Restimulation-induced cell death (RICD) is a critical propriocidal apoptosis program triggered in activated T cells upon robust TCR re-engagement, constraining effector T cell expansion and longevity to prevent collateral tissue damage. 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 newly activated human CD4+ and CD8+ T cells from premature RICD during clonal expansion, with lesser effects noted in terminally differentiated T cells. Both antibody-mediated blockade of PD-1-PD-L1 and SHP2 inhibition increased RICD sensitivity to a similar extent. Conversely, concomitant addition of recombinant PD-L1 with TCR restimulation significantly reduced RICD in a dose-dependent manner, with more pronounced protection noted uopn CD28 coligation. Our ongoing work aims to define the role of recently discovered downstream PD-1 signaling nodes (e.g. PAG, VRK2) and specific pro/anti-apoptotic proteins in this process. These findings present significant implications for understanding how PD-1 blockade may influence apoptosis sensitivity in both normal and exhausted T cells to alter adaptive immune responses. Supported by grants from NIH (R35GM139619)