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

  • Min-Seok Rha
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
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  • Ji Won Han
    Affiliations
    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
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  • Jong Hoon Kim
    Affiliations
    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
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  • June-Young Koh
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
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  • Hye Jung Park
    Affiliations
    Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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  • Soon Il Kim
    Affiliations
    Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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  • Myoung Soo Kim
    Affiliations
    Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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  • Jae Geun Lee
    Affiliations
    Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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  • Hyun Woong Lee
    Affiliations
    Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea
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  • Dong Hyeon Lee
    Affiliations
    Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
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  • Won Kim
    Affiliations
    Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
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  • Jun Yong Park
    Affiliations
    Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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  • Dong Jin Joo
    Correspondence
    Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Tel.: +82-2-2228-2131, fax: +82-2-313-8289
    Affiliations
    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
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  • Su-Hyung Park
    Correspondence
    Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. Tel.: +82-42-350-4248, fax: +82-42-350-4240
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
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  • Eui-Cheol Shin
    Correspondence
    Corresponding authors. Addresses: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. Tel.: +82-42-350-4236, fax: +82-42-350-4240
    Affiliations
    Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
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Published:April 02, 2020DOI:https://doi.org/10.1016/j.jhep.2020.03.033

      Highlights

      • 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.

      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.

      Graphical abstract

      Keywords

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