Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance

Cell Rep. 2020 Oct 20;33(3):108285. doi: 10.1016/j.celrep.2020.108285.


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.

Keywords: BIM; NK cells; apoptosis; proliferation; survival; transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Cell Survival / physiology
  • Female
  • Gene Expression Regulation / genetics
  • Hematopoiesis / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Homeodomain Proteins / physiology
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology


  • Hhex protein, mouse
  • Homeodomain Proteins
  • Interleukin-15
  • Transcription Factors