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Interleukin-35 Suppresses CD8+ T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure

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Abstract

Background

Interleukin (IL)-35 is a newly indentified cytokine and induces immunotolerance via suppression of CD8+ T cell activity in chronic viral hepatitis.

Aims

To investigate the modulatory function of IL-35 to CD8+ T cells in viral hepatitis-induced acute-on-chronic liver failure (ACLF).

Methods

Fifty-five ACLF patients and 21 healthy controls were enrolled. Serum IL-35 concentration was measured by ELISA. Absolute accounts for T cells, immune checkpoint molecules, and cytotoxic molecules in CD8+ T cells were measured by flow cytometry and real-time PCR, respectively. Direct and indirect contact co-culture systems between CD8+ T cells and HepG2 cells were set up. The regulatory function of IL-35 to CD8+ T cells was assessed by measuring lactate dehydrogenase expression and cytokine production.

Results

Serum IL-35 concentration was elevated in ACLF patients and positively correlated with total bilirubin, but negatively correlated with prothrombin time activity. Peripheral CD8+ T cells showed exhausted phenotype in ACLF patients, which manifested as up-regulation of programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) but down-regulation of perforin, granzyme B, and FasL. Recombinant IL-35 stimulation dampened cytotoxicity and interferon-γ production in both direct and indirect contact co-culture systems. This process was accompanied by elevation of PD-1, CTLA-4, and LAG3, as well as reduction of perforin, granzyme B, and FasL in CD8+ T cells.

Conclusion

Elevated IL-35 suppressed both cytolytic and non-cytolytic activity of CD8+ T cells in ACLF patients.

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Abbreviations

ACLF:

Acute-on-chronic liver failure

CTLA-4:

Cytotoxic T-lymphocyte-associated protein-4

ELISA:

Enzyme-linked immunosorbent assay

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

IFN-γ:

Interferon-γ

IL:

Interleukin

LAG-3:

Lymphocyte activation gene-3

LDH:

Lactate dehydrogenase

MIP-1α:

Macrophage inflammatory protein-1α

NC:

Normal control

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed death-1

PTA:

Prothrombin time activity

T-BIL:

Total bilirubin

TNF-α:

Tumor necrosis factor-α

Tregs:

Regulatory T cells

References

  1. Bernal W, Jalan R, Quaglia A, Simpson K, Wendon J, Burroughs A. Acute-on-chronic liver failure. Lancet. 2015;386:1576–1587.

    Article  Google Scholar 

  2. Hernaez R, Sola E, Moreau R, Gines P. Acute-on-chronic liver failure: an update. Gut. 2017;66:541–553.

    CAS  PubMed  Google Scholar 

  3. Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int. 2019;13:1–38.

    Google Scholar 

  4. Arroyo V, Jalan R. Acute-on-Chronic liver failure: definition, diagnosis, and clinical characteristics. Semin Liver Dis. 2016;36:109–116.

    Article  Google Scholar 

  5. Blasco-Algora S, Masegosa-Ataz J, Gutierrez-Garcia ML, Alonso-Lopez S, Fernandez-Rodriguez CM. Acute-on-chronic liver failure: pathogenesis, prognostic factors and management. World J Gastroenterol. 2015;21:12125–12140.

    Article  CAS  Google Scholar 

  6. Hensley MK, Deng JC. Acute on chronic liver failure and immune dysfunction: a mimic of sepsis. Semin Respir Crit Care Med. 2018;39:588–597.

    Article  Google Scholar 

  7. Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–569.

    Article  CAS  Google Scholar 

  8. Wang T, Mei Y, Li Z. Research progress on regulatory B cells in systemic lupus erythematosus. Biomed Res Int. 2019;2019:7948687.

    PubMed  PubMed Central  Google Scholar 

  9. Xue W, Yan D, Kan Q. Interleukin-35 as an emerging player in tumor microenvironment. J Cancer. 2019;10:2074–2082.

    Article  CAS  Google Scholar 

  10. Zhang J, Zhang Y, Wang Q, et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology. 2019;157:13–20.

    Article  CAS  Google Scholar 

  11. Shao X, Ma J, Jia S, Yang L, Wang W, Jin Z. Interleukin-35 suppresses antiviral immune response in chronic hepatitis B virus infection. Front Cell Infect Microbiol. 2017;7:472.

    Article  Google Scholar 

  12. Liu S, Zhang Q, Shao X, Wang W, Zhang C, Jin Z. An immunosuppressive function of interleukin-35 in chronic hepatitis C virus infection. Int Immunopharmacol. 2017;50:87–94.

    Article  CAS  Google Scholar 

  13. Yang L, Shao X, Jia S, Zhang Q, Jin Z. Interleukin-35 dampens CD8(+) T cells activity in patients with non-viral hepatitis-related hepatocellular carcinoma. Front Immunol. 2019;10:1032.

    Article  CAS  Google Scholar 

  14. Yang L, Jia S, Shao X, et al. Interleukin-35 modulates the balance between viral specific CD4(+)CD25(+)CD127(dim/-) regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection. Virol J. 2019;16:48.

    Article  Google Scholar 

  15. Teng DK, Liu Y, Lv YF, et al. Elevated interleukin-35 suppresses liver inflammation by regulation of T helper 17 cells in acute hepatitis B virus infection. Int Immunopharmacol. 2019;70:252–259.

    Article  CAS  Google Scholar 

  16. Li X, Tian L, Dong Y, et al. IL-35 inhibits HBV antigen-specific IFN-gamma-producing CTLs in vitro. Clin Sci (Lond). 2015;129:395–404.

    Article  CAS  Google Scholar 

  17. Wang W, Guo H, Li H, et al. Interleukin-35 gene-modified mesenchymal stem cells protect concanavalin A-induced fulminant hepatitis by decreasing the interferon gamma level. Hum Gene Ther. 2018;29:234–241.

    Article  CAS  Google Scholar 

  18. Zheng XF, Hu XY, Ma B, et al. Interleukin-35 attenuates D-galactosamine/lipopolysaccharide-induced liver injury via enhancing Interleukin-10 production in Kupffer cells. Front Pharmacol. 2018;9:959.

    Article  Google Scholar 

  19. Morissette MC, Parent J, Milot J. Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema. Respir Res. 2007;8:62.

    Article  Google Scholar 

  20. Boegel S, Lower M, Bukur T, Sahin U, Castle JC. A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines. Oncoimmunology. 2014;3:e954893.

    Article  Google Scholar 

  21. Cheng ST, Yuan D, Liu Y, et al. Interleukin-35 level is elevated in patients with chronic hepatitis B virus infection. Int J Med Sci. 2018;15:188–194.

    Article  CAS  Google Scholar 

  22. Fu YP, Yi Y, Cai XY, et al. Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection. Br J Cancer. 2016;114:767–776.

    Article  CAS  Google Scholar 

  23. Zhang MX, Gan W, Jing CY, et al. Overexpression of interleukin-35 in intrahepatic cholangiocarcinoma is a prognostic indicator after curative resection. Cancer Sci. 2018;109:1195–1206.

    Article  CAS  Google Scholar 

  24. Long J, Guo H, Cui S, et al. IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression. Oncotarget. 2016;7:45678–45686.

    Article  Google Scholar 

  25. Li T, Huang Y, Liu P, et al. Lower plasma levels of IL-35 in patients with primary biliary cirrhosis. Tohoku J Exp Med. 2018;244:123–131.

    Article  CAS  Google Scholar 

  26. Yu X, Guo R, Ming D, et al. The transforming growth factor beta1/Interleukin-31 pathway is upregulated in patients with hepatitis B virus-related acute-on-chronic liver failure and is associated with disease severity and survival. Clin Vaccine Immunol. 2015;22:484–492.

    Article  CAS  Google Scholar 

  27. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16:509–523.

    Article  CAS  Google Scholar 

  28. Moreau R. The pathogenesis of ACLF: the inflammatory response and immune function. Semin Liver Dis. 2016;36:133–140.

    Article  CAS  Google Scholar 

  29. Martin-Mateos R, Alvarez-Mon M, Albillos A. Dysfunctional immune response in acute-on-chronic liver failure: it takes two to Tango. Front Immunol. 2019;10:973.

    Article  CAS  Google Scholar 

  30. Ye Y, Liu J, Lai Q, et al. Decreases in activated CD8+ T cells in patients with severe hepatitis B are related to outcomes. Dig Dis Sci. 2015;60:136–145. https://doi.org/10.1007/s10620-014-3297-x

    Article  CAS  PubMed  Google Scholar 

  31. Cao D, Xu H, Guo G, et al. Intrahepatic expression of programmed death-1 and its ligands in patients with HBV-related acute-on-chronic liver failure. Inflammation. 2013;36:110–120.

    Article  CAS  Google Scholar 

  32. Phillips S, Chokshi S, Riva A, Evans A, Williams R, Naoumov NV. CD8(+) T cell control of hepatitis B virus replication: direct comparison between cytolytic and noncytolytic functions. J Immunol. 2010;184:287–295.

    Article  CAS  Google Scholar 

  33. Reiser J, Banerjee A. Effector, memory, and dysfunctional CD8(+) T cell fates in the antitumor immune response. J Immunol Res. 2016;2016:8941260.

    Article  Google Scholar 

  34. Yu W, Wang Y, Guo P. Notch signaling pathway dampens tumor-infiltrating CD8(+) T cells activity in patients with colorectal carcinoma. Biomed Pharmacother. 2018;97:535–542.

    Article  CAS  Google Scholar 

  35. Wang HM, Zhang XH, Feng MM, et al. Interleukin-35 suppresses the antitumor activity of T cells in patients with non-small cell lung cancer. Cell Physiol Biochem. 2018;47:2407–2419.

    Article  CAS  Google Scholar 

  36. Liu MX, Liu QY, Liu Y, et al. Interleukin-35 suppresses antitumor activity of circulating CD8(+) T cells in osteosarcoma patients. Connect Tissue Res. 2019;60:367–375.

    Article  CAS  Google Scholar 

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Funding

This work was funded by the grant from Natural Science Foundation of Jilin Province (No. 20190201047JC) and the grant from Special Health Project of Jilin Province Department of Finance.

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Authors and Affiliations

  1. Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China

    Lanlan Yang, Qian Zhang, Jie Song, Wudong Wang & Zhenjing Jin

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  1. Lanlan Yang
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  2. Qian Zhang
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  3. Jie Song
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  4. Wudong Wang
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  5. Zhenjing Jin
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Correspondence to Zhenjing Jin.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of The Second Hospital of Jilin University and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Yang, L., Zhang, Q., Song, J. et al. Interleukin-35 Suppresses CD8+ T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure. Dig Dis Sci 65, 3614–3623 (2020). https://doi.org/10.1007/s10620-020-06077-w

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