Abstract
Interleukin (IL)-35 plays an immunosuppressive role in infectious diseases, autoimmune disorders, and cancers. However, IL-35 expression and its regulation of CD8+ T cells in infectious mononucleosis (IM) are not fully understood. In this study, three groups of participants were compared, including twenty-three patients of IM without liver inflammation, twenty-eight patients of IM with liver inflammation, and twenty-one controls. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated. CD8+ T cells were purified. Plasma IL-35 was measured by ELISA. PBMCs and CD8+ T cells were stimulated with recombinant human IL-35 in vitro. Perforin and granzyme B secretion was assessed by ELISPOT. Immune checkpoint molecule expression was investigated by flow cytometry. CD8+ T cells were co-cultured with HepG2 cells in direct contact and indirect contact manner. The cytotoxicity of CD8+ T cells was calculated by measuring lactate dehydrogenase release and proinflammatory cytokine expression. There was no significant difference in plasma IL-35 levels between patients with IM without liver inflammation and the controls, but the IL-35 level was notably increased in patients with IM who presented with liver inflammation and negatively correlated with aminotransferase. CD8+ T cells in patients with IM with liver inflammation showed stronger cytotoxicity. IL-35 stimulation inhibited CD8+ T cell-induced target cell death in patients with IM, mainly through suppression of IFN-γ/TNF-α secretion and elevation of immune checkpoint molecule expression, but did not affect perforin or granzyme B secretion. The current data indicated that IL-35 dampened the cytotoxicity of CD8+ T cells in patients with IM probably via repression of cytokine secretion. Elevated IL-35 may protect against CD8+ T cell-induced liver inflammation in patients with IM.
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Abbreviations
- ALT:
-
Alanine aminotransferase
- AST:
-
Asparatate aminotransferase
- CTLA-4:
-
Cytotoxic T-lymphocyte-associated protein 4
- EBV:
-
Epstein-Barr virus
- ELISA:
-
Enzyme-linked immunosorbent assay
- ELISPOT:
-
Enzyme-linked immunospot assay
- FBS:
-
Fetal bovine serum
- HBV:
-
Hepatitis B virus
- IFN-γ:
-
Interferon-γ
- IL:
-
Interleukin
- IM:
-
Infectious mononucleosis
- LAG-3:
-
Lymphocyte activation gene-3
- LDH:
-
Lactate dehydrogenase
- PBMCs:
-
Peripheral blood mononuclear cells
- PD-1:
-
Programmed death-1
- SFC:
-
Spot-forming cells
- T-BIL:
-
Total bilirubin
- TIM-3:
-
T cell immunoglobulin and mucin domain 3
- TNF-α:
-
Tumor necrosis factor-α
- Tregs:
-
Regulatory T cells
- VCA:
-
Viral capsid antigen
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Acknowledgements
This work was supported by a grant from the SPPH Incubator Fund for Development of Science and Technology (2021YJY-19), SPPH Foundation for Development of Science and Technology (2021BJ-26), Xi’an Foundation for Development of Science and Technology [20YXYJ0009(11)], International Science and Technology Cooperation Projects of Shaanxi Province (2022KW-14), and Scientific and Technological Innovation Team of Shaanxi Province (2021TD-40).
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YG, LL, XH, and WZ performed the study. YG, WZ, and YL enrolled the patients. YG, LL, XH, WZ, and YL analyzed the data, and prepared the manuscript. YL designed and supervised the study. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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The current study protocol was in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of Shaanxi Provincial People’s Hospital (No. 2017019).
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Gao, Y., Li, L., Hu, X. et al. Interleukin-35 has a Protective Role in Infectious Mononucleosis-Induced Liver Inflammation Probably by Inhibiting CD8+ T Cell Function. Arch. Immunol. Ther. Exp. 70, 25 (2022). https://doi.org/10.1007/s00005-022-00663-8
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DOI: https://doi.org/10.1007/s00005-022-00663-8