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    Liver-Derived TGF-ß Maintains the EomeshiTbetlo Phenotype of Liver Resident Natural Killer Cells

    Harmon, Cathal and Jameson, Gráinne and Almuaili, Dalal and Houlihan, Diarmaid D. and Hoti, Emir and Geoghegan, Justin and Robinson, Mark W. and O'Farrelly, Cliona (2019) Liver-Derived TGF-ß Maintains the EomeshiTbetlo Phenotype of Liver Resident Natural Killer Cells. Frontiers in Immunology, 10 (1502). ISSN 1664-3224

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    The adult human liver hosts a complex repertoire of liver resident and transient natural killer (NK) cell populations with diverse phenotypes and functions. Liver resident NK cells are CD56bright NK cells defined by a unique expression profile of transcription factors and cell surface markers (EomeshiTbetloTIGIT+CD69+CXCR6+CD49e−). Despite extensive characterization of the phenotype of liver resident NK cells, it remains unclear how factors within the liver microenvironment induce and maintain this unique phenotype. In this study, we have explored the factors regulating the phenotype of liver resident NK cells. Isolation of healthy liver resident NK cells from donor liver perfusate and in vitro culture results in the gradual loss of the characteristic Tbetlo phenotype, with the cells increasing Tbet expression significantly at day 7. This phenotypic loss could be halted through the dose-dependent addition of liver conditioned media (LCM), generated from the ex vivo culture of liver biopsies from healthy organ donors. TGF-b, but not IL-10, replicated the Tbet suppressive effects of LCM in both liver resident and peripheral blood NK cells. Furthermore, blocking TGF-b receptor signaling using the inhibitor SB431542, reversed the effect of LCM treatment on liver resident NK cells, causing the loss of tissue resident Eomeshi Tbetlo phenotype. Our findings identify liver-derived TGF-b as an important component of the liver microenvironment, which acts to regulate and maintain the phenotype of liver resident NK cells.

    Item Type: Article
    Additional Information: Copyright © 2019 Harmon, Jameson, Almuaili, Houlihan, Hoti, Geoghegan, Robinson and O’Farrelly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) ( ). 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. Cite as: Harmon C, Jameson G, Almuaili D, Houlihan DD, Hoti E, Geoghegan J, Robinson MW and O’Farrelly C (2019) Liver-Derived TGF-β Maintains the EomeshiTbetlo Phenotype of Liver Resident Natural Killer Cells. Front. Immunol. 10:1502. doi: 10.3389/fimmu.2019.01502 . Funding: This work was supported by grants from the Health Research Board of Ireland (RP 2008/189 and EIA-2017-013) and a Science Foundation Ireland Investigator Award (12/IA/1667).
    Keywords: TGF-b1; liver-resident NK cell; TBET; microenviroment; Eomes;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 13625
    Identification Number:
    Depositing User: Mark Robinson
    Date Deposited: 26 Nov 2020 14:53
    Journal or Publication Title: Frontiers in Immunology
    Publisher: Frontiers Media
    Refereed: Yes
    Funders: Health Research Board (HRB), Science Foundation Ireland (SFI)
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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