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
Graphical Abstract
Keywords
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Article info
Publication history
Published online: April 02, 2020
Accepted:
March 23,
2020
Received in revised form:
February 26,
2020
Received:
October 23,
2019
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
