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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4573-4580.
Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-08-2975.


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IMMUNOBIOLOGY

Combined deficiency in I{kappa}B{alpha} and I{kappa}B{epsilon} reveals a critical window of NF-{kappa}B activity in natural killer cell differentiation

Sandrine I. Samson, Sylvie Mémet, Christian A. J. Vosshenrich, Francesco Colucci, Odile Richard, Delphine Ndiaye, Alain Israël, and James P. Di Santo

From the Unité des Cytokines et Développement Lymphoïde and Unité de Biologie Moléculaire de l'Expression Génique, Institut Pasteur, Paris, France.

Nuclear factor {kappa}B (NF-{kappa}B) 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-{kappa}B activity impact strongly on B- and T-cell development, little is known about the role for NF-{kappa}B in natural killer (NK) cell differentiation. Inhibitors of NF-{kappa}B (I{kappa}Bs) act to restrain NF-{kappa}B activation. We analyzed the cell-intrinsic effects of deficiencies in 2 I{kappa}B members (I{kappa}B{alpha} and I{kappa}B{epsilon}) on NK cell differentiation. Neither I{kappa}B{alpha} nor I{kappa}B{epsilon} deficiency had major effects on NK cell generation, while their combined absence led to NF-{kappa}B 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-{kappa}B-responsive reporter gene showed increased NF-{kappa}B activity at the stage of NK cell development corresponding to the partial block observed in I{kappa}B{alpha} x I{kappa}B{epsilon}-deficient mice. These results define a critical window in NK cell development in which NF-{kappa}B levels may be tightly controlled. (Blood. 2004;103:4573-4580)


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