Hhex promotes NK cell homeostatis by repressing BIM-dependent apoptosis

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 generated mice that specifically lack Hhex in NK cells. NK cell numbers was dramatically reduced, while NK cell differentiation, IL-15 response and function at the cellular level remained largely normal in the absence of Hhex. Increased IL-15 availability failed 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 revealed that Hhex regulates NK cell survival by repressing expression of the key apoptotic mediator, BIM. These data implicates Hhex as a novel transcription factor essential for NK cell homeostasis and immunity. NK cells were enriched from C57BL/6 mice using the STEMCELL NK cell isolaton kit, cultured for 8 days in the presence of IL-15.