INTERLEUKIN-35 DOWNREGULATES THE IMMUNE RESPONSE OF EFFECTOR CD4+ T CELLS VIA RESTRICTING HIGH MOBILITY GROUP BOX-1 PROTEIN-DEPENDENT AUTOPHAGY IN SEPSIS

Background: Immunosuppression is critically involved in the development of sepsis and is closely associated with poor outcomes. The novel role of the anti-inflammatory cytokine IL-35 in sepsis was examined. Methods: Sepsis was induced by in C57BL/6 mice cecal ligation and puncture (CLP). The impacts of IL-35 on effector CD4(+) T cells were investigated by examining cell proliferation and the Th1/Th2 ratio in the presence of recombinant IL-35 (rIL-35) or anti-IL-35 (EBI3). The regulatory effect of IL-35 on autophagy was evaluated by measuring autophagy markers and autophagic flux in CLP mice in vivo and in activated effector CD4(+) T cells in vitro. Results: IL-35 levels were significantly increased in the serum and spleens of septic mice. rIL-35 administration after CLP further decreased proliferation and the Th1/Th2 ratio in effector CD4(+) T cells and significantly shortened the survival time. Sepsis-induced autophagy activation was protective in effector CD4(+) T cells and was blocked by rIL-35. The inhibitory effect of IL-35 on autophagy was observed in activated effector CD4(+) T cells in vitro, and this effect was mediated by restricting high mobility group box-1 protein (HMGB1) translocation. Conclusion: IL-35 is an immunosuppressive cytokine that impairs CD4(+) T-cell proliferation and differentiation in sepsis, and the effect might be mediated by reducing HMGB1-dependent autophagy.

Automated summary

Immunosuppression plays a crucial role in sepsis development and is closely associated with poor outcomes. This study investigated the novel role of the anti-inflammatory cytokine IL-35 in sepsis. Results showed that IL-35 inhibited CD4(+) T cell proliferation and the Th1/Th2 ratio, and exerted immunosuppressive effects by suppressing HMGB1-dependent autophagy.