Effect of Interleukin-36β on Activating Autophagy of CD4+CD25+ Regulatory T cells and Its Immune Regulation

Background. CD4(+)CD25(+) regulatory T cells (Tregs) play an essential role in sepsis-induced immunosuppression. How, the effects of interleukin 36 (IL-36) cytokines on CD4(+)CD25(+) Tregs and their underlying mechanism(s) in sepsis remain unknown. Methods. Our study was designed to investigate the impacts of IL-36 cytokines on murine CD4(+)CD25(+) Tregs in presence of lipopolysaccharide (LPS) and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). IL-36-activated autophagy was evaluated by autophagy markers, autophagosome formation, and autophagic flux. Results. IL-36 alpha, IL-36 beta, and IL-36 gamma were expressed in murine CD4(+)CD25(+) Tregs. Stimulation of CD4(+)CD25(+) Tregs with LPS markedly up-regulated the expression of these cytokines, particularly IL-36 beta. IL-36 beta strongly suppressed CD4(+)CD25(+) Tregs under LPS stimulation and in septic mice challenged with CLP, resulting in the amplification of T-helper 1 response and the proliferation of effector T cells. Mechanistic studies revealed that IL-36 beta triggered autophagy of CD4(+)CD25(+) Tregs. These effects were significantly attenuated in the presence of the autophagy inhibitor 3-methyladenine or Beclinl knockdown. In addition, early IL-36 beta administration reduced the mortality rate in mice subjected to CLP. Depletion of CD4(+)CD25(+) Tregs before the onset of sepsis obviously abrogated IL-36 beta-mediated protection against sepsis. Conclusions. These findings suggest that IL-36 beta diminishes the immunosuppressive activity of CD4(+)CD25(+ )Tregs by activating the autophagic process, thereby contributing to improvement of the host immune response and prognosis in sepsis.