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

It is well established that the nuclear factor-kappa B (NF-kappa B) 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-kappa B in accessory cell and T or B cell function, but less is known about the role of NF-kappa B in NK cells. However, several studies have demonstrated that these transcription factors are required for NK cell production of IFN-gamma and proliferation. The studies presented here examine the role of two NF-kappa B 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-gamma, but remain unaffected in their capacity to proliferate. In contrast, p50-/- NK cells have enhanced proliferative and IFN-gamma 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-gamma and chromatin immunoprecipitation assays demonstrated the association of p50 with the IFN-gamma promoter of resting NK cells. Consistent with the in vitro studies, in vivo studies with NF-kappa B gene-deficient mice infected with Toxoplasma gondii revealed that the absence of p50 leads to enhanced NK cell proliferation and production of IFN-gamma. Together, these studies define distinct roles for c-Rel and p50 in the function of NK cells.