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

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

Abstract 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 ind...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-04-01
Series:Scientific Reports
Subjects:
PD-L1
pHLIPva
Acidity
T cell
Immunosuppression
Online Access:https://doi.org/10.1038/s41598-025-98135-4
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Summary:Abstract 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.
ISSN:2045-2322

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