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Inducible IFN-γ expression for MHC-I upregulation in devil facial tumor cells

Citation

Ong, CEB and Lyons, AB and Woods, GM and Flies, AS, Inducible IFN-γ expression for MHC-I upregulation in devil facial tumor cells, Frontiers in Immunology, 9 Article 3117. ISSN 1664-3224 (2019) [Refereed Article]


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Copyright Statement

Copyright 2019 Ong, Lyons, Woods and Flies. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.3389/fimmu.2018.03117

Abstract

The Tasmanian devil facial tumor (DFT) disease has led to an 80% reduction in the wild Tasmanian devil (Sarcophilus harrisii) population since 1996. The limited genetic diversity of wild devils and the lack of MHC-I expression on DFT cells have been implicated in the lack of immunity against the original DFT clonal cell line (DFT1). Recently, a second transmissible tumor of independent origin (DFT2) was discovered. Surprisingly, DFT2 cells do express MHC-I, but DFT2 cells appear to be on a trajectory for reduced MHC-I expression in vivo. Thus, much of the ongoing vaccine-development efforts and conservation plans have focused on MHC-I. A major limitation in conservation efforts is the lack of species-specific tools to understand Tasmanian devil gene function and immunology. To help fill this gap, we developed an all-in-one Tet-Off vector system to regulate expression of IFN-γ in DFT cells (DFT1.Tet/IFN-γ). IFN-γ can have negative effects on cell proliferation and viability; thus, doxycycline was used to suppress IFN-γ production whilst DFT1.Tet/IFN-γ cells were expanded in cell culture. Induction of IFN-γ following removal of doxycycline led to upregulation of MHC-I but also the inhibitory checkpoint molecule PD-L1. Additionally, DFT1.Tet/IFN-γ cells were capable of stimulating MHC-I upregulation on bystander wild type DFT cells in co-culture assays in vitro. This system represents a major step forward in DFT disease immunotherapy and vaccine development efforts, and ability to understand gene function in devils. Importantly, the techniques are readily transferable for testing gene function in DFT2 cells and other non-traditional species.

Item Details

Item Type:Refereed Article
Keywords:transmissible tumor, DFTD, IFN-g, MHC-I, Tet-Off system, inducible, PD-L1, apoptosis
Research Division:Medical and Health Sciences
Research Group:Immunology
Research Field:Immunology not elsewhere classified
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Biological Sciences
UTAS Author:Ong, CEB (Ms Chrissy Ong)
UTAS Author:Lyons, AB (Associate Professor Bruce Lyons)
UTAS Author:Woods, GM (Professor Gregory Woods)
UTAS Author:Flies, AS (Dr Andy Flies)
ID Code:130419
Year Published:2019
Funding Support:Australian Research Council (DE180100484)
Web of Science® Times Cited:1
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-01-24
Last Modified:2020-04-02
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