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IB-Deficient Mice: Reduction of One T Cell Precursor Subspecies and Enhanced Ig Isotype Switching and Cytokine Synthesis¹

Sylvie Mémet^2,*, Dhafer Laouini, Jean-Charles Epinat^3,*, Simon T. Whiteside^4,*, Bertrand Goudeau^*, Dana Philpott, Samer Kayal^§, Philippe J. Sansonetti, Patrick Berche^§, Jean Kanellopoulos and Alain Israël^*

^* Unité de Biologie Moléculaire de l’Expression Génique, Centre National de la Recherche Scientifique Unité de Recherche Associée 1773, Unité de Biologie Moléculaire du Gène, Institut National de la Santé et de la Recherche Médicale U277, and Unité de Pathogénie Microbienne Moléculaire, Institut National de la Santé et de la Recherche Médicale U389, Institut Pasteur, Paris, France; and ^§ Institut National de la Santé et de la Recherche Médicale U411, Faculté de Médecine Necker, Paris, France

Three major inhibitors of the NF-B/Rel family of transcription factors, IB, IBß, and IB, have been described. To examine the in vivo role of the most recently discovered member of the IB family, IB, we generated a null allele of the murine IB gene by replacement of all coding sequences with nlslacZ. Unlike IB nullizygous mice, mice lacking IB are viable, fertile, and indistinguishable from wild-type animals in appearance and histology. Analysis of ß-galactosidase expression pattern revealed that IB is mainly expressed in T cells in the thymus, spleen, and lymph nodes. Flow cytometric analysis of immune cell populations from the bone marrow, thymus, spleen, and lymph nodes did not show any specific differences between the wild-type and the mutant mice, with the exception of a reproducible 50% reduction of the CD44^-CD25⁺ T cell subspecies. The IB-null mice present constitutive up-regulation of IgM and IgG1 Ig isotypes together with a further increased synthesis of these two isotypes after immunization against T cell-dependent or independent Ags. The failure of observable augmentation of constitutive nuclear NF-B/Rel-binding activity is probably due to compensatory mechanisms involving IB and IBß, which are up-regulated in several organs. RNase-mapping analysis indicated that IL-1, IL-1ß, IL-1Ra, and IL-6 mRNA levels are constitutively elevated in thioglycolate-elicited IB-null macrophages in contrast to GM-CSF, G-CSF, and IFN-, which remain undetectable.

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