IL-15 Activates Liver Sinusoidal Mucosal-associated Invariant T Cells to Exert TCR/MR1-independent Innate-like Cytotoxicity

Abstract

Abstract Mucosal-associated invariant T (MAIT) cells are the most dominant population of innate-like T cells in the human liver and predominantly localized in liver sinusoids. MAIT cells can be activated by MR1-dependent TCR stimulation or cytokines such as IL-12 and IL-18. However, effects of IL-15 on MAIT cells have not been comprehensively studied, particularly in the aspect of their innate-like cytotoxic activity. In the present study, we examined effects of IL-15 on liver sinusoidal MAIT cells obtained from donor liver perfusates during liver transplantation. IL-15 activated MAIT cells to have a cytotoxic phenotype and induces cellular proliferation. Moreover, IL-15-activated liver sinusoidal MAIT cells exerted innate-like cytotoxicity that is independent of TCR and MR1. Increased target cell conjugation and NKG2D-dependent stimulation were responsible for innate-like cytotoxicity of IL-15-activated MAIT cells, and PI3K–mTOR pathway was critically required for IL-15-induced innate-like cytotoxicity. Furthermore, we observed an increased NKG2D expression in intrahepatic MAIT cells from patients with acute hepatitis A, in which liver injury is known to be mediated by IL-15-induced innate-like cytotoxicity of T cells (Immunity 2018, 48:161). In summary, our data demonstrate IL-15 activates liver sinusoidal MAIT cells to exert TCR/MR1-independent cytotoxicity, and suggest a potential role of liver sinusoidal MAIT cells in immune responses or immunopathogenesis in liver diseases.