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 - 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 - BIM
KW - NK cells
KW - apoptosis
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 -