title: Ikaros Is a Negative Regulator of B1 Cell Development and Function.
abstract: B1 B cells secrete most of the circulating natural antibodies and are considered key effector cells of the innate immune response. However, B1 cell-associated antibodies often cross-react with self-antigens, which leads to autoimmunity, and B1 cells have been implicated in cancer. How B1 cell activity is regulated remains unclear. We show that the Ikaros transcription factor is a major negative regulator of B1 cell development and function. Using conditional knock-out mouse models to delete Ikaros at different locations, we show that Ikaros-deficient mice exhibit specific and significant increases in splenic and bone marrow B1 cell numbers, and that the B1 progenitor cell pool is increased ∼10-fold in the bone marrow. Ikaros-null B1 cells resemble WT B1 cells at the molecular and cellular levels, but show a down-regulation of signaling components important for inhibiting proliferation and immunoglobulin production. Ikaros-null B1 cells hyper-react to TLR4 stimulation and secrete high amounts of IgM autoantibodies. These results indicate that Ikaros is required to limit B1 cell homeostasis in the adult.
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors: Alejandra
authors: A
authors: Macias-Garcia
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France, heizmann@igbmc.fr.
authors: Beate
authors: B
authors: Heizmann
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors: MacLean
authors: M
authors: Sellars
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors: Patricia
authors: P
authors: Marchal
authors: Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, 67000 Strasbourg, France.
authors: Hayet
authors: H
authors: Dali
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France, Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, 67000 Strasbourg, France, UFR Médecine, Université de Strasbourg, 67000 Strasbourg, France.
authors: Jean-Louis
authors: JL
authors: Pasquali
authors: Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, 67000 Strasbourg, France, Institut d'Etudes Avancées, Université de Strasbourg, 67000 Strasbourg, France, and.
authors: Sylviane
authors: S
authors: Muller
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France scpk@igbmc.fr.
authors: Philippe
authors: P
authors: Kastner
authors: From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France, scpk@igbmc.fr.
authors: Susan
authors: S
authors: Chan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007075:Immunoglobulin M; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor
keywords: B cells; Ikaros; autoimmune disease; differentiation; gene regulation; immunology; leukemia