Opposing roles of NF-κB family members in the regulation of NK cell proliferation and production of IFN-γ

Abstract

It is well established that the nuclear factor-κB (NF-κB) family of transcription factors participates in the regulation of many aspects of innate and adaptive immunity. The majority of these reports have focused on the role of NF-κB in accessory cell and T or B cell function, but less is known about the role of NF-κB in NK cells. However, several studies have demonstrated that these transcription factors are required for NK cell production of IFN-γ and proliferation. The studies presented here examine the role of two NF-κB members, c-Rel and p50, in NK cell function. In vitro data revealed that in the absence of c-Rel, NK cells have a defect in their ability to secrete IFN-γ, but remain unaffected in their capacity to proliferate. In contrast, p50−/− NK cells have enhanced proliferative and IFN-γ responses compared with wild-type NK cells. The latter findings suggest a role for p50 as a negative regulator of NK cell production of IFN-γ and chromatin immunoprecipitation assays demonstrated the association of p50 with the IFN-γ promoter of resting NK cells. Consistent with the in vitro studies, in vivo studies with NF-κB gene-deficient mice infected with Toxoplasma gondii revealed that the absence of p50 leads to enhanced NK cell proliferation and production of IFN-γ. Together, these studies define distinct roles for c-Rel and p50 in the function of NK cells.