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MAIT Cell Dysregulation Correlates with Conjugated Bilirubin Level in Chronic Hepatitis B Virus Infection
Yu Liu
Peng Zhu
Wei Wang
Xiaosheng Tan
Chuanqiao Liu
Yingshan Chen
Rongjuan Pei
Xue Cheng
Mi Wu
Qing Guo
Hongmei Liang
Zhihui Liang
Jia Liu
Yang Xu
Xiongwen Wu
Xiufang Weng
First published: 20 October 2020
https://doi.org/10.1002/hep.31602
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1002/hep.31602
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Abstract
Background & Aims
Mucosal‐associated invariant T (MAIT) cells are non‐conventional T cells restricted to MHC class I‐related protein 1 (MR1). They are highly abundant in human liver, and activated by TCR‐dependent and TCR‐independent mechanisms to exhibit rapid innate‐like effector responses. However, the roles of MAIT cells in chronic HBV infection still remain obscure. This study aims to test their antiviral potential, and investigate their dynamic changes and regulating factors during chronic HBV infection.
Approach & Results
Blood samples from 257 chronic HBV‐infected patients were enrolled, and non‐tumor liver specimens were collected from 58 HBV‐infected hepatocellular carcinoma patients. Combining cell culture experiments and human data, we showed that MAIT cells had strong cytotoxicity against HBV‐transfected hepatocytes in a MR1‐dependent way. However, circulating and hepatic MAIT cells in HBV‐infected patients decreased significantly compared with controls. Correlation analysis suggested MAIT cell frequency was associated with disease progression and inversely correlated with serum conjugated bilirubin level. In particular, conjugated bilirubin not only directly promoted MAIT cell activation and apoptosis, but also impaired TCR‐induced proliferation and expansion of MAIT cells which could be partially rescued by IL‐2 in the absence of conjugated bilirubin. Albeit MAIT cells from patients with high conjugated bilirubin level showed decreased cytokine producing capacity, the increased TCR‐dependent antiviral cytokine production suggested MAIT cell as an important guardian of chronic hepatitis B with high conjugated bilirubin.
Conclusion
We reveal MR1‐dependent anti‐HBV potential of MAIT cells and identify conjugated bilirubin as a major factor dysregulating its frequency and function in chronic HBV‐infected patients, suggesting a novel therapeutic target for MAIT cell‐based immunity against chronic HBV infection.
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发表于 2020-10-24 09:13