Hhex Is Essential for NK Cell Persistence by Repressing Bcl2l11-Dependent Apoptosis

Abstract

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. However, whether Hhex is intrinsically required throughout NK cell development or for NK cell function remains unknown. To investigate this, we generated mice that specifically lack Hhex in NK cells. We found Hhex to be intrinsically required for NK cell homeostasis and subsequent in vivo viral and tumor immunity. NK cell differentiation, IL-15 responsiveness and function on a cellular level were largely normal in the absence of Hhex. Unexpectedly, increased IL-15 availability failed to rescue 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 was required for NK cell survival by repressing BIM expression, a key apoptotic mediator in NK cells. Thus this study identifies Hhex as a novel transcription factor essential for NK cell homeostasis and immunity.

Keywords: NK cells, Transcription Factors, Apoptosis, Innate Immunity, immunotherapy