Min-Seok Rha1, Ji Won Han2, Jong Hoon Kim3, June-Young Koh1, Hye Jung Park4, Soon Il Kim5, Myoung Soo Kim5, Jae Geun Lee5, Hyun Woong Lee6, Dong Hyeon Lee7, Won Kim7, Jun Yong Park4, Dong Jin Joo8, Su-Hyung Park9, Eui-Cheol Shin10. 1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. 2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Republic of Korea. 3. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea. 4. Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. 5. Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. 6. Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea. 7. Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea. 8. Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address: djjoo@yuhs.ac. 9. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. Electronic address: park3@kaist.ac.kr. 10. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. Electronic address: ecshin@kaist.ac.kr.
Abstract
BACKGROUND & AIMS: 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. 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. LAY SUMMARY: 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.
BACKGROUND & AIMS: 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. 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. LAY SUMMARY: 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.
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Authors: Katie Healy; Andrea Pavesi; Tiphaine Parrot; Michał J Sobkowiak; Susanne E Reinsbach; Haleh Davanian; Anthony T Tan; Soo Aleman; Johan K Sandberg; Antonio Bertoletti; Margaret Sällberg Chen Journal: JHEP Rep Date: 2021-06-11
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