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
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.
