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During this transition phase, c-myc controls both proliferation and apoptosis ( 19), depending on signals provided by cytokines ( 20).
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As Blimp-1 is gradually upregulated from the mature B cell stage to the plasma cell ( 13), the expression of c-myc is progressively turned off ( 18). Blimp-1 has also been shown recently to regulate the expression of c-myc in mature B cells ( 17). Transfection of Blimp-1 into the BCL1 CW13.20-3B3 mature B cell line (hereafter referred to as 3B3) induces IgM secretion, J chain upregulation, and Syndecan-1 expression ( 13). Blimp-1 and its human homologue PRDI-BF1 ( 14, 15) are zinc finger proteins that contain four Kruppel-like zinc fingers as well as a number of other domains that may mediate protein– protein interactions ( 13, 16). We have previously shown that IL-2 and IL-5 upregulate the expression of the B lymphocyte–induced maturation protein (Blimp-1) 1 in mature B cells ( 13). Transcription factors that regulate the survival of developing B cells at different points along this pathway remain largely unknown. The selected B cell clones then interact with T cells that provide them with additional survival signals, induce isotype switching ( 11, 12), and aid in their differentiation into plasma or memory cells. The surviving cells interact with follicular dendritic cells that supply proliferative, antiapoptotic signals ( 7, 8) and upregulate the expression of multiple receptors required for T cell interaction ( 9, 10). After being exposed to the appropriate T cell help, they proliferate and relocate to germinal centers ( 5), where they are subjected to negative selection before the onset of somatic mutation ( 6). Upon antigen encounter, these long-lived circulating cells are retained in secondary lymphoid organs. Once mature, the recruitment of new B cells to the long-lived recirculating B cell pool depends on a positive selection process that takes place in the splenic periarteriolar lymphoid sheath (PALS reference 4). The majority of nonreactive and self-reactive clones are eliminated in the bone marrow at the pro– ( 1, 2) and pre–B stages ( 3). We propose that Blimp-1 expression defines a checkpoint beyond which fully activated B cells proceed to the plasma cell stage, whereas immature and partially activated cells are eliminated at this point.ĭifferentiation of B lymphocytes into plasma cells depends on their continuous exposure to prodifferentiation and antiapoptosis signals. Truncation mutants indicate that the induction of the apoptotic response relies mainly on 69 amino acids within Blimp-1's proline-rich domain.
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A similar effect was noticed when Blimp-1 was expressed in the mature L10A and the immature WEHI-231 lines, indicating this may be a general effect at earlier stages of the B cell development, and distinct from the ability of Blimp-1 to induce maturation in late stages of differentiation. At the same time, the ectopic expression of Blimp-1 in these partially activated cells induces an apoptotic response that also can be suppressed by the same dominant negative protein. This blasting effect and the increase in IgM secretion that follows it can be blocked by a dominant negative form of Blimp-1. After interleukin (IL)-2 and IL-5 stimulation, the BCL1 3B3 cells differentiate into centrocyte-like cells, whereas the BCL1 5B1b cells blast and appear to be blocked at the centroblast stage. We have transfected Blimp-1 into two sublines of the BCL1 B cell lymphoma that represent distinct stages of B cell development in secondary lymphoid tissues. The B lymphocyte–induced maturation protein (Blimp-1) upregulates the expression of syndecan-1 and J chain and represses that of c-myc.