Abstract
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.
Highlights
Natural Killer (NK) cells are innate immune cells with anti-tumor and anti-viral activity [1, 2]
NK cells develop from NK progenitor (NKp) cells, which originated from Common Lymphoid Progenitor (CLP) cells (Figure 1B)
A pilot experiment indicated a potential reduction of both CD27+ and CD11b+ differentiated NK cells in the lymph nodes (LN) and liver of c-Rel-/- compared to wild type (WT) mice (Supplementary Figure 1D)
Summary
Natural Killer (NK) cells are innate immune cells with anti-tumor and anti-viral activity [1, 2]. These cells express a wide range of activating and inhibitory receptors that upon engagement by cognate ligands on target tumor cells regulate their anti-tumor activity [3, 4]. Granzymes are a family of serine proteases with gzmb being the most studied member of this family [15,16,17] Under pathological conditions such as in cancer, prf and gzmb are reported to be downregulated in NK cells compromising its cytotoxic function leading to NK cell exhaustion [18,19,20,21]. We c-Rel Regulates NK Cell Function reported that inhibition of GSK3 signaling led to increased NK cell cytotoxicity via NF-kB activation [22]
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