Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance

Wilford Goh; Sebastian Scheer; Jacob T. Jackson; Soroor Hediyeh-Zadeh; Rebecca B. Delconte; Iona S. Schuster; Christopher E. Andoniou; Jai Rautela; Mariapia A. Degli-Esposti; Melissa J. Davis; Matthew P. McCormack; Stephen L. Nutt; Nicholas D. Huntington

Cell Reports (Oct 2020)

Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance

Wilford Goh,
Sebastian Scheer,
Jacob T. Jackson,
Soroor Hediyeh-Zadeh,
Rebecca B. Delconte,
Iona S. Schuster,
Christopher E. Andoniou,
Jai Rautela,
Mariapia A. Degli-Esposti,
Melissa J. Davis,
Matthew P. McCormack,
Stephen L. Nutt,
Nicholas D. Huntington

Affiliations

Wilford Goh: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia
Sebastian Scheer: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
Jacob T. Jackson: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia
Soroor Hediyeh-Zadeh: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
Rebecca B. Delconte: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia
Iona S. Schuster: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, 6009, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
Christopher E. Andoniou: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, 6009, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
Jai Rautela: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia; oNKo-Innate Pty Ltd., 27 Norwood Cres, Moonee Ponds, Victoria, 3039, Australia
Mariapia A. Degli-Esposti: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, 6009, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
Melissa J. Davis: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia; Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia
Matthew P. McCormack: The Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, 3004, Australia
Stephen L. Nutt: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia
Nicholas D. Huntington: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 3010, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia; oNKo-Innate Pty Ltd., 27 Norwood Cres, Moonee Ponds, Victoria, 3039, Australia; Corresponding author

Journal volume & issue: Vol. 33, no. 3
p. 108285

Abstract

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Summary: 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. To determine if Hhex is intrinsically required throughout NK cell development or for NK cell function, we generate mice that specifically lack Hhex in NK cells. NK cell frequency is dramatically reduced, while NK cell differentiation, IL-15 responsiveness, and function at the cellular level remain largely normal in the absence of Hhex. Increased IL-15 availability fails to fully reverse 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 reveal that Hhex regulates NK cell survival by directly binding Bcl2l11 (Bim) and repressing expression of this key apoptotic mediator. These data implicate Hhex as a transcriptional regulator of NK cell homeostasis and immunity.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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