Interleukin-35 Suppresses CD8 + T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure
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ORIGINAL ARTICLE
Interleukin‑35 Suppresses CD8+ T Cell Activity in Patients with Viral Hepatitis‑Induced Acute‑on‑Chronic Liver Failure Lanlan Yang1 · Qian Zhang1 · Jie Song1 · Wudong Wang1 · Zhenjing Jin1 Received: 18 November 2019 / Accepted: 13 January 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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 C D8+ 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 C D8+ 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. Keywords Interleukin-35 · CD8+ T cells · Acute-on-chronic liver failure · Immunotolerance 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 * Zhenjing Jin [email protected] 1
Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun 130041, Jilin Province, China
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
Introduction Acute-on-chronic liver failure (ACLF) is a complex syndrome, which is characterized by an acute deterioration of liver function in the background of a previously diagnosed or undiagnosed c
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