The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype
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Published version
Author(s)
Type
Journal Article
Abstract
The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.
Date Issued
2019-09-11
Date Acceptance
2019-08-29
Citation
Frontiers in Immunology, 2019, 10, pp.1-15
ISSN
1664-3224
Publisher
Frontiers Media
Start Page
1
End Page
15
Journal / Book Title
Frontiers in Immunology
Volume
10
Copyright Statement
© 2019 Cuff, Sillito, Dertschnig, Hall, Luong, Chakraverty and Male. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor
Wellcome Trust
Identifier
https://www.frontiersin.org/articles/10.3389/fimmu.2019.02180/full
Grant Number
105677/Z/14/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
NK cells
ILC1
obesity
NAFLD
immunometabolism
TGF beta
NATURAL-KILLER-CELLS
T-BET
MATERNAL OBESITY
INFLAMMATION
DELETION
HOMEOSTASIS
FIBROSIS
PROGRAMS
PROMOTE
DISEASE
ILC1
NAFLD
NK cells
TGFβ
immunometabolism
obesity
1107 Immunology
Publication Status
Published
Article Number
280
Date Publish Online
2019-09-11