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<p>Programmed cell death–ligand 1 (PD-L1)/PD-1 axis is crucial for maintenance of immune homeostasis and its impairment partially accounts for the pathogenesis of inflammatory diseases. Hence, augmenting PD-L1/PD-1 signals represents a novel strategy to prevent destructive inflammation and induce immune tolerance. Recently, we developed a new cargo by conjugating the ectodomain of PD-L1 with pHLIP, a low pH-responding and membrane-inserting peptide, and demonstrated its potent immune-suppressive activity under weakly acidic (pH6.1) conditions in vitro. Herein, we further showed that PD-L1-pHLIP (termed as PD-L1-pHLIP<sub>wt</sub>) responded well to weakly acidic buffer, but not in nearly neutral pH (pH6.8) solutions. To overcome this obstacle, pHLIP<sub>wt</sub> was replaced by a variant harboring two mutations (Asp14Gla and Asp25Aad) and PD-L1 ectodomain was conjugated to the N-terminus of pHLIP variant via sulfo-SMCC linker (termed as PD-L1-pHLIP<sub>va</sub>). PD-L1-pHLIP<sub>va</sub> potently inhibited T effector function including proliferation, activation as well as proinflammatory cytokine release in nearly neutral pH buffer through PD-L1/PD-1 interaction. The inhibitory function of PD-L1-pHLIP<sub>va</sub> was attributed to more amounts of PD-L1 anchored on the surface of several types of immune cells compared with PD-L1-pHLIP<sub>wt</sub>. Given that the niche in the lesions of inflammation is weakly acidic even nearly neutral pH, PD-L1-pHLIP<sub>va</sub> represents a new arsenal to potentially dampen excessive inflammatory reactions.</p>

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Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月18日

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  • Hang Zheng,
  • Mianjing Wang,
  • Junjuan Feng,
  • Yuting Zhang,
  • Haiyan Wu,
  • Min Zhang,
  • He Xiao,
  • Chunxia Qiao,
  • Jing Wang,
  • Longlong Luo,
  • Xinying Li,
  • Jiannan Feng,
  • Yuanqiang Zheng,
  • Yi Wang,
  • Dongsheng Sheng,
  • Guojiang Chen

摘要

Programmed cell death–ligand 1 (PD-L1)/PD-1 axis is crucial for maintenance of immune homeostasis and its impairment partially accounts for the pathogenesis of inflammatory diseases. Hence, augmenting PD-L1/PD-1 signals represents a novel strategy to prevent destructive inflammation and induce immune tolerance. Recently, we developed a new cargo by conjugating the ectodomain of PD-L1 with pHLIP, a low pH-responding and membrane-inserting peptide, and demonstrated its potent immune-suppressive activity under weakly acidic (pH6.1) conditions in vitro. Herein, we further showed that PD-L1-pHLIP (termed as PD-L1-pHLIPwt) responded well to weakly acidic buffer, but not in nearly neutral pH (pH6.8) solutions. To overcome this obstacle, pHLIPwt was replaced by a variant harboring two mutations (Asp14Gla and Asp25Aad) and PD-L1 ectodomain was conjugated to the N-terminus of pHLIP variant via sulfo-SMCC linker (termed as PD-L1-pHLIPva). PD-L1-pHLIPva potently inhibited T effector function including proliferation, activation as well as proinflammatory cytokine release in nearly neutral pH buffer through PD-L1/PD-1 interaction. The inhibitory function of PD-L1-pHLIPva was attributed to more amounts of PD-L1 anchored on the surface of several types of immune cells compared with PD-L1-pHLIPwt. Given that the niche in the lesions of inflammation is weakly acidic even nearly neutral pH, PD-L1-pHLIPva represents a new arsenal to potentially dampen excessive inflammatory reactions.