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Downregulation of Programmed Death-1 Pathway Promoting CD8 + T Cell Cytotoxicity in Primary Biliary Cholangitis

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Abstract

Background

Primary biliary cholangitis (PBC) is an autoimmune disease. CD8 + T cell (CTLs) cytotoxicity played a crucial rule in of PBC with unclear detailed pathogenesis.

Aims

The role of the programmed death-1 (PD-1) pathway in CD8 + T cell cytotoxicity in patients with PBC was determined.

Methods

We recruited 69 patients with PBC and 57 healthy controls (HCs). PD-1 pathway in peripheral CD8 + T cells and related cytokines were detected, and gene expression levels were detected. Immunofluorescence staining of PD-1/PD-L1 was performed on liver tissue. PD-1 ± CTLs were cocultured with human intrahepatic biliary epithelial cells (HiBECs) to measure CTL cytotoxicity, proliferation and cytokine levels and HiBEC apoptosis. The upstream signaling pathway of PD-1 was detected.

Results

PBC patients exhibited Tbet gene upregulation and PD-1 downregulation in CTLs, with PD-1 expression reduced in CTLs and PD-L1 reduced in the liver portal region relative to HCs. Higher plasma IL-10, interferon-γ and transforming growth factor-β concentrations were observed in the PBC group than the HC group. In CTL and HiBEC coculture experiment, compared with PD-1- CTLs, PD-1 + CTLs exhibited weaker cytotoxicity, less proliferation and lower cytokine production. When the system was blocked by anti-PD-1 antibodies, these effects were antagonized.

Conclusions

PD-1 expression in CD8 + T cells decreased, and PD-1 pathway-related cytokines changed in patients with PBC. PD-1/PD-L1 pathway silencing increased CD8 + T cell proliferation, related cytokine production and CTL cytotoxic effects on HiBECs in coculture experiment. The PD-1/PD-L1 pathway might represent an important pathway in the immunological mechanism underlying PBC.

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Acknowledgments

The authors apologize to all colleagues whose work has not been separately cited or discussed here due to limitations in space or knowledge.

Funding

This work was partially supported by grants from the Natural Science Foundation of Beijing Municipality (CN) (Youth Project) [Grant No. 7194307, 2019], the National Natural Science Foundation of China (Outstanding Youth Foundation) [Grant No. 81501414], and the National Key Research and Development Program of China [Grant No. 2016YFA010100, 2016].

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Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China

    Shuo Zhang, Li Wang, Hua Chen, Liling Zhao, Jinlei Sun, Sainan Bian, Zhilei Chen, Tihong Shao, Yunjiao Yang & Fengchun Zhang

  2. Department of Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China

    Xixi Tao

  3. Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China

    Yongzhe Li

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  1. Shuo Zhang
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Correspondence to Fengchun Zhang.

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Ethical approval was obtained from the Research Ethics Committee of Peking Union Medical College Hospital (No. S-283).

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Zhang, S., Tao, X., Wang, L. et al. Downregulation of Programmed Death-1 Pathway Promoting CD8 + T Cell Cytotoxicity in Primary Biliary Cholangitis. Dig Dis Sci 67, 2981–2993 (2022). https://doi.org/10.1007/s10620-021-07165-1

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  • DOI: https://doi.org/10.1007/s10620-021-07165-1

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