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The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype

Cuff, AO; Sillito, F; Dertschnig, S; Hall, A; Tu, VL; Chakraverty, R; Male, V; (2019) The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype. Frontiers in Immunology , 10 , Article 2180. 10.3389/fimmu.2019.02180. Green open access

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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 toward 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.

Type: Article
Title: The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2019.02180
Publisher version: https://doi.org/10.3389/fimmu.2019.02180
Language: English
Additional information: Copyright © 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.
Keywords: NK cells, ILC1, obesity, NAFLD, immunometabolism, TGFβ
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10082492
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