The University of Western Australia, Centre for Ophthalmology and Visual Science, Immunology and Virology Program; Lions Eye Institute - Centre for Experimental Immunology; Monash University, Biomedicine Discovery Institute, Department of Microbiology
The Walter and Eliza Hall Institute of Medical Research; University of Melbourne - Department of Medical Biology; Monash University, Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology; oNKo-Innate Pty Ltd.
The University of Western Australia, Faculty of Medical and Health Sciences, Centre for Ophthalmology and Visual Science, Immunology and Virology Program; Lions Eye Institute - Centre for Experimental Immunology; Monash University, Biomedicine Discovery Institute, Department of Microbiology
University of Melbourne - Department of Medical Biology; Monash University, Biomedicine Discovery Institute, Department of Microbiology; oNKo-Innate Pty Ltd.
Hhex encodes a homeobox transcriptional regulator important for embryonic development and hematopoiesis. Hhex is highly expressed in NK cells and its germline deletion results in significant defects in lymphoid development, including NK cells. However, whether Hhex is intrinsically required throughout NK cell development or for NK cell function remains unknown. To investigate this, we generated mice that specifically lack Hhex in NK cells. We found Hhex to be intrinsically required for NK cell homeostasis and subsequent in vivo viral and tumor immunity. NK cell differentiation, IL-15 responsiveness and function on a cellular level were largely normal in the absence of Hhex. Unexpectedly, increased IL-15 availability failed to rescue NK lymphopenia following conditional Hhex deletion, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches revealed that Hhex was required for NK cell survival by repressing BIM expression, a key apoptotic mediator in NK cells. Thus this study identifies Hhex as a novel transcription factor essential for NK cell homeostasis and immunity.
Keywords: NK cells, Transcription Factors, Apoptosis, Innate Immunity, immunotherapy
Goh, Wilford and Jackson, Jacob T. and Hediyeh-zadeh, Soroor and Delconte, Rebecca B. and Andoniou, Christopher E. and Rautela, Jai and Degli-Esposti, Mariapia A. and Davis, Melissa J. and McCormack, Matthew P. and Nutt, Stephen L. and Huntington, Nicholas David, Hhex Is Essential for NK Cell Persistence by Repressing
Bcl2l11-Dependent Apoptosis (January 2, 2020). Available at SSRN: https://ssrn.com/abstract=3512977 or http://dx.doi.org/10.2139/ssrn.3512977
This version of the paper has not been formally peer reviewed.
The University of Western Australia, Faculty of Medical and Health Sciences, Centre for Ophthalmology and Visual Science, Immunology and Virology Program
Crawley Australia
Lions Eye Institute - Centre for Experimental Immunology
Nedlands Australia
Monash University, Biomedicine Discovery Institute, Department of Microbiology
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