PD-1 signaling serves a dual role in suppressing T cell activation but also in protecting from activation-induced cell death

Abstract PD1/PDL1 interactions exert potent inhibitory effects on T cell responses. Inhibition of this pathway results in greater T cell responses and is increasingly used in cancer immunotherapy but the long-term effects of PD1 inhibition on T cell activation responses remain unclear. We hypothesized that these gains in proliferation and activation on T cells over time may result in greater T cell loss due to apoptosis via activation induced cell death (AICD). We investigated this using both mouse and human T cell models of activation. T cells from wild-type or PD1−/− mice were activated in vitro by a variety of stimuli. We observed significantly increased total T cell numbers, as well as expression of Ki67 and CD69 in the PD-1−/− T cells compared to controls. However, we identified that this increase was accompanied by increased cell death and apoptosis at later time points. Using in vivo adoptive transfer models (allogeneic & xenogeneic) in which PD-1−/− murine cells, or human T cells given in tandem with PD-1 checkpoint blockade we assessed PD-1 inhibition in vivo on T cell activation, proliferation, and apoptosis. We observed early expansion and activation of murine PD-1−/− cells in the allogeneic environment compared to controls. Furthermore, human T cells transplanted into immunodeficient mice given anti-PD1 also had greater activation and proliferation. Yet, this was followed by a sharper contraction and increased apoptosis identified through decreased cell numbers and increased Annexin V staining. These data suggest PD-1 regulates T cell activation as a means of protection, but when this balance is manipulated, T cells experience a “short term gain” for a “long term loss” in which cells undergo greater early activation at the cost of AICD. Supported by National Institute of Health grant numbers NIH RO1 HL140921 (WJM), National Institute of Health grant numbers NIH RO1 CA214048 (WJM).