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
Bernal W, Jalan R, Quaglia A, Simpson K, Wendon J, Burroughs A. Acute-on-chronic liver failure. Lancet. 2015;386:1576–1587.
Hernaez R, Sola E, Moreau R, Gines P. Acute-on-chronic liver failure: an update. Gut. 2017;66:541–553.
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.
Arroyo V, Jalan R. Acute-on-Chronic liver failure: definition, diagnosis, and clinical characteristics. Semin Liver Dis. 2016;36:109–116.
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.
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.
Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–569.
Wang T, Mei Y, Li Z. Research progress on regulatory B cells in systemic lupus erythematosus. Biomed Res Int. 2019;2019:7948687.
Xue W, Yan D, Kan Q. Interleukin-35 as an emerging player in tumor microenvironment. J Cancer. 2019;10:2074–2082.
Zhang J, Zhang Y, Wang Q, et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology. 2019;157:13–20.
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.
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.
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.
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.
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.
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.
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.
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.
Morissette MC, Parent J, Milot J. Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema. Respir Res. 2007;8:62.
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.
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.
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.
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.
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.
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.
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.
Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16:509–523.
Moreau R. The pathogenesis of ACLF: the inflammatory response and immune function. Semin Liver Dis. 2016;36:133–140.
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.
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
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.
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.
Reiser J, Banerjee A. Effector, memory, and dysfunctional CD8(+) T cell fates in the antitumor immune response. J Immunol Res. 2016;2016:8941260.
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.
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.
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.
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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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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DOI: https://doi.org/10.1007/s10620-020-06077-w