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

 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 
 JOURNAL OF HEPATOLOGY, Vol.73(3) : 640-650, 2020-09 
Journal Title
Issue Date
Cytotoxicity ; Hepatitis ; IL-15 ; Mucosal-associated invariant T cells ; Virus
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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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Kim, Soon Il(김순일) ORCID logo https://orcid.org/0000-0002-0783-7538
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Park, Hye Jung(박혜정) ORCID logo https://orcid.org/0000-0002-1862-1003
Lee, Jae Geun(이재근) ORCID logo https://orcid.org/0000-0002-6722-0257
Lee, Hyun Woong(이현웅) ORCID logo https://orcid.org/0000-0002-6958-3035
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
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