NF-κB c-Rel Is Dispensable for the Development but Is Required for the Cytotoxic Function of NK Cells

Front Immunol. 2021 Apr 29:12:652786. doi: 10.3389/fimmu.2021.652786. eCollection 2021.


Natural Killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. We found that germline deficiency of NF-κB c-Rel results in a marked decrease in cytotoxic function of NK cells, both in vitro and in vivo, with no significant differences in the stages of NK cell development. We found that c-Rel binds to the promoters of perforin and granzyme B, two key proteins required for NK cytotoxicity, and controls their expression. We generated a NK cell specific c-Rel conditional knockout to study NK cell intrinsic role of c- Rel and found that both global and conditional c-Rel deficiency leads to decreased perforin and granzyme B expression and thereby cytotoxic function. We also confirmed the role of c-Rel in perforin and granzyme B expression in human NK cells. c-Rel reconstitution rescued perforin and granzyme B expressions in c-Rel deficient NK cells and restored their cytotoxic function. Our results show a previously unknown role of c-Rel in transcriptional regulation of perforin and granzyme B expressions and control of NK cell cytotoxic function.

Keywords: NF-κB c-Rel; NK cell; cytotoxicity; granzyme; perforin (Prf1).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytotoxicity, Immunologic* / genetics
  • Granzymes / metabolism
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Melanoma, Experimental
  • Mice
  • Mice, Knockout
  • Models, Biological
  • NF-kappa B / metabolism*
  • Pore Forming Cytotoxic Proteins / genetics
  • Pore Forming Cytotoxic Proteins / metabolism
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / metabolism*


  • Cytokines
  • NF-kappa B
  • Pore Forming Cytotoxic Proteins
  • Proto-Oncogene Proteins c-rel
  • Granzymes