Interleukin-15-induced cytotoxicity of human liver $CD8^{+}$ mucosal-associated invariant T cells

Abstract

Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in human liver, can be activated by MHC class I-related molecule 1 (MR1)-dependent TCR stimulation or by cytokines in the absence of TCR stimulation. However, whether MAIT cells can exert TCR/MR1-independent cytolytic activity remains unclear. Here, I examined the mechanisms underlying TCR/MR1-independent innate-like cytotoxicity of cytokine-activated liver MAIT cells. I also investigated the phenotype and function of MAIT cells from patients with viral hepatitis. IL-15-stimulated MAIT cells exerted granzyme B-dependent innate-like cytotoxicity in the absence of TCR/MR1 interaction. PI3K–mTOR signaling, NKG2D ligation, and CD2-mediated conjugate formation were all critically required for this IL-15-induced innate-like cytotoxicity. MAIT cells from patients with acute hepatitis A (AHA) exhibited activated and cytotoxic phenotypes with higher NKG2D expression. The innate-like cytotoxicity of MAIT cells was significantly increased in patients with AHA and correlated with serum alanine aminotransferase levels. In summary, the results demonstrate that liver MAIT cells activated by IL-15 exert NKG2D-dependent innate-like cytotoxicity in the absence of TCR/MR1 engagement. Furthermore, the innate-like cytotoxicity of MAIT cells is associated with liver injury in patients with AHA, suggesting that MAIT cells contribute to immune-mediated liver injury in liver disease.