Human liver CD8+ MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15

• Published in: Journal of hepatology Vol. 73; no. 3; pp. 640 - 650
• Main Authors: Rha, Min-Seok, Han, Ji Won, Kim, Jong Hoon, Koh, June-Young, Park, Hye Jung, Kim, Soon Il, Kim, Myoung Soo, Lee, Jae Geun, Lee, Hyun Woong, Lee, Dong Hyeon, Kim, Won, Park, Jun Yong, Joo, Dong Jin, Park, Su-Hyung, Shin, Eui-Cheol
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2020
• Subjects: Cytotoxicity; Hepatitis; IL-15; Mucosal-associated invariant T cells; Virus; Virus; Mucosal-associated invariant T cells; Hepatitis; IL-15; Cytotoxicity
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2020.03.033

Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in the human liver, can be activated by cytokines during viral infection without TCR stimulation. Here, we examined the mechanisms underlying TCR/MR1-independent innate-like cytotoxicity of cytokine-activated liver MAIT cells. We also examined the phenotype and function of MAIT cells from patients with acute viral hepatitis. We obtained liver sinusoidal mononuclear cells from donor liver perfusate during liver transplantation and examined the effect of various cytokines on liver MAIT cells using flow cytometry and in vitro cytotoxicity assays. We also obtained peripheral blood and liver-infiltrating T cells from patients with acute hepatitis A (AHA) and examined the phenotype and function of MAIT cells using flow cytometry. 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 critically required for this IL-15-induced innate-like cytotoxicity. MAIT cells from patients with 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. Taken together, 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. Immune-mediated liver injury commonly occurs during viral infections of the liver. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the human liver. Herein, we have identified a mechanism by which MAIT cells circumvent conventional T cell receptor interactions to exert cytotoxicity. We show that this innate-like cytotoxicity is increased during acute hepatitis A virus infection and correlates with the degree of hepatocyte injury. [Display omitted] •MAIT cells activated by IL-15 exert TCR/MR1-independent, innate-like cytotoxicity.•Innate-like cytotoxicity of MAIT cells is dependent on NKG2D, granzyme B, and CD2.•PI3K–mTOR signaling is required for innate-like cytotoxicity of MAIT cells.•MAIT cells exhibit activated and cytotoxic phenotypes during acute hepatitis A.•MAIT cells may contribute to liver injury during acute hepatitis A.