RESUMEN
Oct-2 and OBF-1 (also called OCA-B or Bob-1) are B cell-specific transcription factors that bind to the conserved octamer site of immunoglobulin promoters, yet their role in immunoglobulin transcription has remained unclear. We generated mice in which the lymphoid compartment was reconstituted with cells that lack both Oct-2 and OBF-1. Even in the absence of these two transcription factors, B cells develop normally to the membrane immunoglobulin M-positive (IgM+) stage and immunoglobulin gene transcription is essentially unaffected. These observations imply that the ubiquitous factor Oct-1 plays a previously unrecognized role in the control of immunoglobulin gene transcription and suggest the existence of another, as yet unidentified, cofactor. In addition, both factors are essential for germinal center formation, although OBF-1 is more important than Oct-2 for IgG production after immunization.
Asunto(s)
Linfocitos B/citología , Linfocitos B/inmunología , Proteínas de Unión al ADN/deficiencia , Genes de Inmunoglobulinas , Transactivadores/deficiencia , Factores de Transcripción/deficiencia , Animales , Linfocitos B/metabolismo , Secuencia de Bases , Diferenciación Celular , Cartilla de ADN/genética , Proteínas de Unión al ADN/genética , Centro Germinal/citología , Centro Germinal/inmunología , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Ratones , Ratones Noqueados , Modelos Biológicos , Factor 2 de Transcripción de Unión a Octámeros , ARN/genética , ARN/metabolismo , Transactivadores/genética , Factores de Transcripción/genética , Transcripción GenéticaRESUMEN
OBF-1 is a B cell-restricted transcriptional coactivator that is recruited to octamer-containing promoters by interacting with the POU domain of Oct-1 or Oct-2. We have shown earlier that mice lacking OBF-1 were dramatically impaired in their ability to mount humoral immune responses and did not develop germinal centers in the spleen; however, they had a largely normal B cell development in the bone marrow. In this study, we demonstrate that OBF-1-deficient mice also have an early defect in B cell development and show that OBF-1-/- immature B cells are greatly impaired at the transition from the bone marrow to the spleen. In addition, when the OBF-1 mutation is combined to a mutation in the gene encoding Bruton's tyrosine kinase, a striking phenotype is observed. These double-deficient animals lack peripheral B cells and have virtually no serum Igs, thus closely resembling human X chromosome-linked agammaglobulinemia.