Combined deficiency in IkappaBalpha and IkappaBepsilon reveals a critical window of NF-kappaB 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 (NK) 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 (IkappaBalpha and IkappaBepsilon) on NK cell differentiation. Neither IkappaBalpha nor IkappaBepsilon 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 IkappaBepsilon-deficient mice. These results define a critical window in NK cell development in which NF-kappaB levels may be tightly controlled.
Samson
Sandrine I
SI
Unité des Cytokines et Développement Lymphoïde, Institut Pasteur, 25 rue du Dr Roux, 75742 Paris, France.
Mémet
Sylvie
S
Vosshenrich
Christian A J
CA
Colucci
Francesco
F
Richard
Odile
O
Ndiaye
Delphine
D
Israël
Alain
A
Di Santo
James P
JP
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002678:Chimera; D016207:Cytokines / Q000096:biosynthesis; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000276:immunology
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C491366:Nfkbie protein, mouse; D011518:Proto-Oncogene Proteins; D000072000:NF-KappaB Inhibitor alpha