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Human liver CD8+ MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15
Journal of Hepatology ( IF 18.946 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.jhep.2020.03.033
Min-Seok Rha; Ji Won Han; Jong Hoon Kim; June-Young Koh; Hye Jung Park; Soon Il Kim; Myoung Soo Kim; Jae Geun Lee; Hyun Woong Lee; Dong Hyeon Lee; Won Kim; Jun Yong Park; Dong Jin Joo; Su-Hyung Park; Eui-Cheol Shin

Background & Aims Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in 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. Methods 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. Results 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. Conclusions 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 in liver disease.
更新日期:2020-04-21

 

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