Combined deficiency in IκBα and lκBα reveals a critical window of NF-κB activity in natural killer cell differentiation

Nuclear factor kappaB (NF-kappaB) transcription factors are key regulators of immune, inflammatory, and acute-phase responses and are also implicated in the control of cell proliferation and apoptosis. While perturbations in NF-kappaB activity impact strongly on B- and T-cell development, little is known about the role for NF-kappaB in natural killer (INK) cell differentiation. Inhibitors of NF-kappaB (IkappaBs) act to restrain NF-kappaB activation. We analyzed the cell-intrinsic effects of deficiencies in 2 IkappaB members (IkappaBa and IkappaBis an element of) on NK cell differentiation. Neither IkappaBalpha nor IkappaBis an element of deficiency had major effects on NK cell generation, while their combined absence led to NF-kappaB hyperactivation, resulting in reduced NK cell numbers, incomplete NK cell maturation, and defective interferon gamma (IFN-gamma) production. Complementary analysis of transgenic mice expressing an NF-kappaB-responsive reporter gene showed intrinsic effects of deficiencies in 2 IkappaB members (IkappaBalpha and IkappaBis an element of) on NK cell differentiation. Neither IkappaBalpha nor IkappaBis an element of deficiency had major effects on NK cell generation, while their combined absence led to NF-kappaB hyperactivation, resulting in reduced NK cell numbers, incomplete NK cell maturation, and defective interferon gamma (IFN-gamma) production. Complementary analysis of transgenic mice expressing an NF-kappaB-responsive reporter gene showed increased NF-kappaB activity at the stage of NK cell development corresponding to the partial block observed in IkappaBalpha x IkappaBis an element of-deficient mice. These results define a critical window in NK cell development in which NF-kappaB levels may be tightly controlled.