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

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.

Investigation of Immune Responses in Giant African Snail, Achatina immaculata, against a Two-Round Lipopolysaccharide Challenge

“…Simultaneously, the expression levels of downstream effectors in the TLR4 signaling were measured, and the expression of ADAM17 and PRF1 was significantly upregulated after the second stimulation. As reported, NF-κB released by AKT activates IκB kinase (IKK) and can bind directly to the ADAM17 and PRF1 promoters to enhance their expression [42][43][44]. Furthermore, ADAM17 can trigger the release cytokines and other inflammatory proteins in a way that eliminate foreign antigens, and PRF1 can directly target Gram-negative bacteria and certain pathogenic parasites by forming pores on the membranes of target cells, eventually causing cell lysis [43][44][45][46].…”

GSK‐3β/β‐catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells

“…29 c-Rel, one of the NF-κB family members, plays a crucial role in the killing function of NK cells. 30 NF-κB dipolymer binds to the κB site and promotes or inhibits target gene transcription. 31 Other studies have revealed that GSK-3β enhances the DNA binding activity of NF-κB, which regulates the transcription of genes.…”

“…When the Wnt signal is active, inactivation of GSK‐3β causes dephosphorylation of β‐catenin and is stably present in cells 29 . c‐Rel, one of the NF‐κB family members, plays a crucial role in the killing function of NK cells 30 . NF‐κB dipolymer binds to the κB site and promotes or inhibits target gene transcription 31 .…”

In vitro machine learning-based CAR T immunological synapse quality measurements correlate with patient clinical outcomes

“…In this study, we did not directly compare the SPE method with the conventional approaches. The conventional approaches to predict clinical outcomes in response to CAR therapy include multi-parametric flow cytometry, in vitro killing assays (e.g., short-term 4-h killing assay and long-term killing assay), cytokine productions by IsoPlexis [ 55 , 56 ], classic ELISA, and flow cytometry, RNA-Sequence of CAR-T cells [ 57 ], and other in vitro and in vivo animal models [ 4 ]. To ensure that transduced cells retain similar phenotypic and functional characteristics, researchers typically measure CAR-T cell growth kinetics and immunophenotype for 2–4 weeks after expansion [ 4 , 9 ].…”