在缺乏T细胞受体（TCR）信号的情况下，通过细胞因子信号激活记忆T细胞的旁观激活只能以非特异性抗原的方式来扩大T细胞效应反应。尽管程序化细胞死亡蛋白1（PD-1）在特异性抗原T细胞反应中的作用已有大量研究，但其在旁观T细胞反应中的作用尚不清楚。我们研究了PD-1途径在人类和小鼠非特异性记忆T细胞旁观激活中的作用，并观察到在体外PD-1+ T细胞的激活和增殖较激活的PD-1-细胞群体低。在经历高剂量IL-2治疗的小鼠和癌症患者中，也观察到PD-1-记忆细胞群体的更高激活和增殖反应，这与体外表型相一致。在体上，PD-1的抑制效应可通过体内PD-1抑制剂阻断或使用PD-1-/-小鼠的记忆T细胞来逆转。有趣的是，通过PD-1信号抑制的旁观激活T细胞的激活增加也导致由激活诱导的细胞死亡（AICD）引起的细胞凋亡增加和最终T细胞的丧失。这些结果表明PD-1/PD-Ligand 1（PD-L1）途径抑制了旁观激活的记忆T细胞反应，同时也保护了细胞免受AICD的影响。

Bystander activation of memory T cells occurs via cytokine signaling alone in the absence of T cell receptor (TCR) signaling and provides a means of amplifying T cell effector responses in an antigen-nonspecific manner. While the role of Programmed Cell Death Protein 1 (PD-1) on antigen-specific T cell responses is extensively characterized, its role in bystander T cell responses is less clear. We examined the role of the PD-1 pathway during human and mouse non-antigen-specific memory T cell bystander activation and observed that PD-1+ T cells demonstrated less activation and proliferation than activated PD-1- populations in vitro. Higher activation and proliferative responses were also observed in the PD-1- memory population in both mice and patients with cancer receiving high-dose IL-2, mirroring the in vitro phenotypes. This inhibitory effect of PD-1 could be reversed by PD-1 blockade in vivo or observed using memory T cells from PD-1-/- mice. Interestingly, increased activation through abrogation of PD-1 signaling in bystander-activated T cells also resulted in increased apoptosis due to activation-induced cell death (AICD) and eventual T cell loss in vivo. These results demonstrate that the PD-1/PD-Ligand 1 (PD-L1) pathway inhibited bystander-activated memory T cell responses but also protected cells from AICD.