Interleukin-35 has a Protective Role in Infectious Mononucleosis-Induced Liver Inflammation Probably by Inhibiting CD8⁺ T Cell Function

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.