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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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-98135-4 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hang Zheng |
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| description | 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. |
| format | Article |
| id | doaj-art-3a47a8b68f384772ac5d78cc1e75abbd |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-3a47a8b68f384772ac5d78cc1e75abbd2025-08-20T03:18:42ZengNature PortfolioScientific Reports2045-23222025-04-0115111410.1038/s41598-025-98135-4Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1Hang Zheng0Mianjing Wang1Junjuan Feng2Yuting Zhang3Haiyan Wu4Min Zhang5He Xiao6Chunxia Qiao7Jing Wang8Longlong Luo9Xinying Li10Jiannan Feng11Yuanqiang Zheng12Yi Wang13Dongsheng Sheng14Guojiang Chen15Research Center of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical UniversityResearch Center of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical UniversityResearch Center of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical UniversityInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyInstitute of Pharmacology and ToxicologyResearch Center of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical UniversityDepartment of Hematology, The Fifth Medical Center, Chinese PLA General HospitalDepartment of Thoracic surgery, The Fifth Medical Center, Chinese PLA General HospitalInstitute of Pharmacology and ToxicologyAbstract 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.https://doi.org/10.1038/s41598-025-98135-4PD-L1pHLIPvaAcidityT cellImmunosuppression |
| spellingShingle | 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 Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1 Scientific Reports PD-L1 pHLIPva Acidity T cell Immunosuppression |
| title | Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1 |
| title_full | Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1 |
| title_fullStr | Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1 |
| title_full_unstemmed | Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1 |
| title_short | Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1 |
| title_sort | improved acid driven inhibition of effector t cell function by a phlip variant conjugated pd l1 |
| topic | PD-L1 pHLIPva Acidity T cell Immunosuppression |
| url | https://doi.org/10.1038/s41598-025-98135-4 |
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