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 | CELL PRESS | Published : 2020
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 th..View full abstract
Awarded by National Health and Medical Research Council (NHMRC) of Australia
Awarded by NHMRC Investigator Fellowship
Awarded by Victorian Cancer Agency grant
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).