IL-33 promotes antiviral CD8+ T cells through the mTORC1 pathway and limits liver injury via recruiting immunosuppressive neutrophils

Abstract

Viral hepatitis is a major public health problem worldwide. The multifunctional IL-33 is critical for the activity of antiviral cytotoxic T lymphocytes (CTLs) in persistent viral infection; however, the signaling mechanism defining how IL-33 promotes immune cell activation is unclear. In addition, IL-33 can also recruit neutrophils, suggesting that it may regulate liver injury through modulating myeloid cell functions. In this study, we revealed an essential role for endogenous IL-33 regarding antiviral T cell responses in lymphocytic choriomeningitis virus (LCMV) infection. Deficiency of CTL effector activity in IL-33 knockout (KO) mice was restored by recombinant IL-33 treatment. Mechanistically, IL-33 induced CD8+ T cell activation and proliferation through the PI3K/mTORC1 singling pathway. Interestingly, IL-33 treatment also induced significant neutrophil accumulation, but decreased CD8+ T cell numbers, in infected liver. By depleting neutrophils in vivo, we demonstrated that neutrophils played an immunomodulatory role and attenuated liver injury by inhibiting infiltration and the activity of CTLs at the contraction stage of immune response. IL-33-induced immunosuppressive neutrophils expressed higher levels of arginase-1 through type 2 innate lymphoid cells (ILC2)/IL-13/STAT6 axis. This study, therefore, demonstrates a dual role of IL-33 in promoting antiviral CD8+ T cell response at the initial stage, but inducing immunomodulatory neutrophils through induction of ILC2 to limit liver injury during the contraction stage of immune response.