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

doi:10.1016/j.celrep.2020.108285

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

Cell Rep. 2020 Oct 20;33(3):108285. doi: 10.1016/j.celrep.2020.108285.

Affiliations

¹ 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.
² Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
⁴ Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, 6009, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
⁵ 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.
⁶ 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.
⁷ The Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, 3004, Australia.
⁸ 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. Electronic address: [email protected].

PMID: 33086067
DOI: 10.1016/j.celrep.2020.108285

Abstract

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.

Keywords: BIM; NK cells; apoptosis; proliferation; survival; transcriptional regulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Cell Differentiation / physiology
Cell Proliferation / physiology
Cell Survival / physiology
Female
Gene Expression Regulation / genetics
Hematopoiesis / genetics
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Homeodomain Proteins / physiology
Interleukin-15 / genetics
Interleukin-15 / immunology
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism*
Male
Mice
Mice, Inbred C57BL
Signal Transduction / physiology
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription Factors / physiology

Substances

Hhex protein, mouse
Homeodomain Proteins
Interleukin-15
Transcription Factors