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Downregulated VISTA enhances Th17 differentiation and aggravates inflammation in patients with acute-on-chronic liver failure

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Abstract

Background and aims

Persistent inflammatory response and immune activation are the core mechanisms underlying acute-on-chronic liver failure (ACLF). Previous studies have shown that deficiency of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) exacerbates the progression of inflammatory diseases. We aimed to clarify the role of VISTA in the pathogenesis of ACLF.

Methods

Blood and liver samples were collected from healthy subjects, stable cirrhosis, and ACLF patients to characterize VISTA expression and function. An ACLF mouse model was used to ascertain potential benefits of anti-VISTA monoclonal antibody (mAb) treatment.

Results

VISTA expression was significantly reduced in the naïve and central memory CD4+ T cells from patients with ACLF. The expression of VISTA on CD4+ T cells was associated with disease severity and prognosis. VISTA downregulation contributed to the activation and proliferation of CD4+ T cells and enhanced the differentiation of T helper 17 cells (Th17) and secretion of inflammatory cytokines through the activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Moreover, agonistic anti-VISTA mAb treatment inhibited the activation and cytokine production of CD4+ T cells and reduced mortality and liver inflammation of the ACLF mice.

Conclusions

The decreased expression of VISTA may facilitate development of Th17 cells and promote the progression of inflammation in ACLF patients. These findings are helpful for elucidating the pathogenesis of ACLF and for the identification of new drug targets.

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Availability of data and materials

All relevant data supporting the conclusions of this study are displayed within this manuscript. More detailed data is available from the corresponding author upon request.

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Acknowledgement

We thank Dr. Haiyan Lv (Fudan University) for her helpful suggestions during the study.

Funding

This study was financially supported by the National Natural Science Foundation of China (81871640, 82172255), Shanghai Shen Kang Hospital Development Center (No. SHDC12019116), and Shanghai Key Clinical Specialty Construction Program (ZK2019B24).

Author information

Author notes

  1. Yao Zhang and Xueyun Zhang contributed equally to this study.

Authors and Affiliations

  1. Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China

    Yao Zhang, Xueyun Zhang, Jiajia Han, Yifei Guo, Feifei Yang, Fahong Li, Haoxiang Zhu, Zhongliang Shen, Yuxian Huang, Richeng Mao & Jiming Zhang

  2. Key Laboratory of Medical Molecular Virology, MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Fahong Li, Zhongliang Shen, Richeng Mao & Jiming Zhang

  3. Department of Infectious Diseases, Jing’An Branch of Huashan Hospital, Fudan University, Shanghai, China

    Jiming Zhang

  4. Department of Hepatitis Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China

    Yuxian Huang

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Contributions

YZ and XYZ: made the study concept and design; statistical analysis and drafting of manuscript was done by YZ. XYZ, JJH and YFG: conducted some experimental studies; FFY, FHL and HXZ: helped experimental design; YZ, XYZ, and ZLS: conducted the collection of clinical data and sample; critical revision of manuscript done for important intellectual content was done by YXH, RCM and JMZ; JMZ: supervised the whole project. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Yuxian Huang, Richeng Mao or Jiming Zhang.

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Conflict of interest

The Yao Zhang, Xueyun Zhang, Jiajia Han, Yifei Guo, Feifei Yang, Fahong Li, Haoxiang Zhu, Zhongliang Shen, Yuxian Huang, Richeng Mao, Jiming Zhang have no conflicts of interest to declare.

Ethical approval

This study was conducted in compliance with the principles of the Helsinki Declaration and was approved by the Ethical Committee of Huashan Hospital of Fudan University and the Ethical Committee of the Shanghai Public Health Clinical Center.

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All of the patients provided a written informed consent.

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Zhang, Y., Zhang, X., Han, J. et al. Downregulated VISTA enhances Th17 differentiation and aggravates inflammation in patients with acute-on-chronic liver failure. Hepatol Int 17, 1000–1015 (2023). https://doi.org/10.1007/s12072-023-10505-0

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