Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China.
Front Immunol. 2021 Dec 23;12:794226. doi: 10.3389/fimmu.2021.794226. eCollection 2021.
Programmed cell death-ligand 1 (PD-L1)/PD-1 axis is critical for maintenance of immune homeostasis by limiting overactivation of effector T-cell responses. The impairment of PD-L1/PD-1 signals play an important role in the pathogenesis of inflammatory diseases, making this pathway an ideal target for novel therapeutics to induce immune tolerance. Given weakly acidic environment as a putative hallmark of inflammation, in this study we designed a new cargo by linking the ectodomain of murine PD-L1 to the N terminus of pHLIPs, a low pH-responding and membrane-insertion peptide, and demonstrated its potent immune-suppressive activity. Specifically, PD-L1-pHLIP spanned the cellular membrane and perfectly recognized its ligand PD-1 in acidic buffer. Immobile PD-L1-pHLIP actively inhibited T-cell proliferation and IFN-γ production. Importantly, soluble PD-L1-pHLIP retained its function to dampen T-cell responses under acidic condition instead of neutral aqueous solution. Overall, these data suggest that PD-L1-pHLIP has potentials to be a novel therapeutic avenue for T-cell-mediated inflammatory diseases.
程序性细胞死亡配体 1（PD-L1）/PD-1 轴对于通过限制效应 T 细胞反应的过度激活来维持免疫稳态至关重要。PD-L1/PD-1 信号的损伤在炎症性疾病的发病机制中起着重要作用，使该途径成为诱导免疫耐受的新型治疗药物的理想靶标。鉴于弱酸性环境是炎症的一个假定特征，在这项研究中，我们通过将小鼠 PD-L1 的胞外结构域与 pHLIPs 的 N 端连接来设计一种新的载体，pHLIPs 是一种对低 pH 有反应的和膜插入肽，并证明了它具有强大的免疫抑制活性。具体来说，PD-L1-pHLIP 跨越细胞膜，并在酸性缓冲液中完美地识别其配体 PD-1。固定化的 PD-L1-pHLIP 可积极抑制 T 细胞增殖和 IFN-γ 的产生。重要的是，可溶性 PD-L1-pHLIP 在酸性条件下保留了其功能，以抑制 T 细胞反应，而不是在中性水溶液中。总的来说，这些数据表明，PD-L1-pHLIP 有可能成为治疗 T 细胞介导的炎症性疾病的一种新的治疗途径。
