TY - JOUR
T1 - Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance
AU - Goh, Wilford
AU - Scheer, Sebastian
AU - Jackson, Jacob T.
AU - Hediyeh-Zadeh, Soroor
AU - Delconte, Rebecca B.
AU - Schuster, Iona S.
AU - Andoniou, Christopher E.
AU - Rautela, Jai
AU - Degli-Esposti, Mariapia A.
AU - Davis, Melissa J.
AU - McCormack, Matthew P.
AU - Nutt, Stephen L.
AU - Huntington, Nicholas D.
N1 - Funding Information:
We wish to thank C. Quillici, T. Camilleri, T. Kratina, E. Surgenor, F. Souza-Fonseca-Guimaraes, L. O'Reilly, and S. Wilcox for providing technical assistance and reagents. E. Vivier provided Ncr1iCre mice, and M.J. Herold provided Bimfl/fl mice. We are grateful to WEHI Bioservices, monoclonal antibody facility, flow cytometry laboratory, and Clinical Translational Centre. W.G. is supported by a Melbourne International Research Scholarship. This work is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (GNT1124784, GNT1066770, GNT1057852, GNT1124907, GNT1057812, GNT1049407, GNT1027472, and GNT1184615 to N.D.H.) and an NHMRC Investigator Fellowship (GNT1195296 to N.D.H.). N.D.H. is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust, Melanoma Research Alliance Young Investigator Award, an Ian Potter Foundation equipment grant, the National Foundation for Medical Research and Innovation (NFMRI) John Dixon Hughes Medal, and a CLIP grant from Cancer Research Institute. S.L.N. is a NHMRC SPRF Fellow (GNT1155342). M.A.D.-E. is a NHMRC PRF Fellow (GNT1119298). J.R. was supported by a Victorian Cancer Agency grant (ECSG18020). W.G. J.T.J. R.B.D. C.E.A. I.S.S. S.S. and J.R. designed and performed experiments. S.H.-Z. and S.S. provided bioinformatics analysis and input into interpretation of results. N.D.H. S.L.N. M.P.M. M.J.D. and M.A.D.-E. supervised experimental design and provided input into interpretation of results. M.P.M. provided Hhexfl/fl mice. W.G. S.L.N. and N.D.H. wrote the manuscript with editorial input from all authors. N.D.H. and J.R. are cofounders and shareholders in oNKo-Innate. The other authors declared no competing interests.
Funding Information:
We wish to thank C. Quillici, T. Camilleri, T. Kratina, E. Surgenor, F. Souza-Fonseca-Guimaraes, L. O’Reilly, and S. Wilcox for providing technical assistance and reagents. E. Vivier provided Ncr1 iCre mice, and M.J. Herold provided Bim fl/fl mice. We are grateful to WEHI Bioservices, monoclonal antibody facility, flow cytometry laboratory, and Clinical Translational Centre. W.G. is supported by a Melbourne International Research Scholarship. This work is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia ( GNT1124784 , GNT1066770 , GNT1057852 , GNT1124907 , GNT1057812 , GNT1049407 , GNT1027472 , and GNT1184615 to N.D.H.) and an NHMRC Investigator Fellowship ( GNT1195296 to N.D.H.). N.D.H. is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust , Melanoma Research Alliance Young Investigator Award, an Ian Potter Foundation equipment grant, the National Foundation for Medical Research and Innovation (NFMRI) John Dixon Hughes Medal, and a CLIP grant from Cancer Research Institute . S.L.N. is a NHMRC SPRF Fellow ( GNT1155342 ). M.A.D.-E. is a NHMRC PRF Fellow ( GNT1119298 ). J.R. was supported by a Victorian Cancer Agency grant ( ECSG18020 ).
Publisher Copyright:
© 2020 The Authors
PY - 2020/10/20
Y1 - 2020/10/20
N2 - 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.
AB - 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.
KW - apoptosis
KW - BIM
KW - NK cells
KW - proliferation
KW - survival
KW - transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85092630541&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.108285
DO - 10.1016/j.celrep.2020.108285
M3 - Article
C2 - 33086067
AN - SCOPUS:85092630541
SN - 2211-1247
VL - 33
JO - Cell Reports
JF - Cell Reports
IS - 3
M1 - 108285
ER -