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.

中文翻译：

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人肝 CD8+ MAIT 细胞对 IL-15 产生不依赖于 TCR/MR1 的先天样细胞毒性

背景和目的 粘膜相关不变 T (MAIT) 细胞是人类肝脏中最丰富的先天样 T 细胞，可在病毒感染期间被细胞因子激活而无需 TCR 刺激。在这里，我们研究了细胞因子激活的肝 MAIT 细胞的 TCR/MR1 非依赖性先天样细胞毒性的机制。我们还检查了急性病毒性肝炎患者的 MAIT 细胞的表型和功能。方法我们在肝移植过程中从供体肝灌注液中获得肝窦单核细胞，并使用流式细胞术和体外细胞毒性试验检测各种细胞因子对肝 MAIT 细胞的影响。我们还获得了急性甲型肝炎 (AHA) 患者的外周血和肝脏浸润 T 细胞，并使用流式细胞术检查了 MAIT 细胞的表型和功能。结果 在没有 TCR/MR1 相互作用的情况下，IL-15 刺激的 MAIT 细胞发挥了依赖于颗粒酶 B 的先天样细胞毒性。PI3K-mTOR 信号传导、NKG2D 连接和 CD2 介导的偶联物形成是这种 IL-15 诱导的先天样细胞毒性所必需的。来自 AHA 患者的 MAIT 细胞表现出活化和细胞毒性表型，具有更高的 NKG2D 表达。MAIT 细胞的先天样细胞毒性在 AHA 患者中显着增加，并与血清丙氨酸转氨酶水平相关。结论 综上所述，结果表明，在没有 TCR/MR1 参与的情况下，由 IL-15 激活的肝脏 MAIT 细胞发挥 NKG2D 依赖性先天样细胞毒性。此外，MAIT 细胞的先天样细胞毒性与 AHA 患者的肝损伤有关，