DEFECTIVE B-CELL RECEPTOR-MEDIATED RESPONSES IN MICE LACKING THE ETS PROTEIN, SPI-B

Spi-B is a hematopoietic-specific Ets family transcription factor clos ely related to PU.1. Previous gene targeting experiments have shown th at PU.1 is essential for the production of both lymphocytes and monocy tes. We have now generated mice with a null mutation at the Spi-B locu s. Unlike PU.1 mutant mice, Spi-B-/- mice are viable, fertile and poss ess mature B and T lymphocytes. However, Spi-B-/- mice exhibit severe abnormalities in B cell function and selective T cell-dependent humora l immune responses, First, although Spi-B-/- splenic B cells respond n ormally to lipopolysaccharide stimulation in vitro, these B cells prol iferate poorly and die in response to B cell receptor (surface IgM) cr oss-linking. Secondly, Spi-B-/- mice display abnormal T-dependent anti genic responses in vivo and produce low levels of antigen-specific IgG (1), IgG(2a) and IgG(2b) after immunization. Finally, Spi-B-/- mice sh ow a dramatic defect in germinal center formation and maintenance. In contrast to wild-type animals, germinal centers in Spi-B-/- mice are s maller and short-lived with significantly increased numbers of apoptot ic B cells, Taken together, these results demonstrate that Spi-B is es sential for antigen-dependent expansion of B cells, T-dependent immune responses and maturation of normal germinal centers in vivo.