The differentiation of mature B cells into antibody-secreting plasma cells is controlled by the presence or absence of transcription factors, including B-lymphocyte-induced maturation protein 1 (BLIMP1) and B-cell lymphoma 6 (BCL6), respectively. Recent work has enabled the genes that are targeted by these transcriptional repressors to be identified and has provided an insight into how they interact to control terminal B-cell differentiation.

Forced expression of BLIMP1 drives mature B cells to differentiate into plasma cells. Targets of BLIMP1-dependent repression, such as c-MYC, CIITA and PAX5, have been identified previously, but the control of these genes is not sufficient to explain how BLIMP1 regulates terminal B-cell differentiation. To investigate this further, Shaffer and colleagues carried out a DNA-microarray analysis of the changes in gene expression that are induced by BLIMP1, and their findings are now published in Immunity.

Shaffer et al. identified 228 genes that are repressed and 32 genes that are induced in B-cell lines that express BLIMP1 compared with control cells. In many cases, microarray targets were confirmed by independent messenger-RNA and protein-expression assays. BLIMP1 was shown to promote B-cell terminal differentiation by turning off the expression of genes that are associated with cell-cycle progression, and DNA synthesis and repair, as well as those that are involved in mature B-cell function. These include several transcription factors, such as BCL6 and two newly identified targets, SPI-B and ID3. BLIMP1 also downregulates the expression of genes that are required for immunoglobulin class switching (such as AID, KU70, KU86, DNA-PKCs and STAT6), thereby inhibiting this process. Of the genes that are turned on, of particular interest is the transcriptional activator XBP1, which is a crucial regulator of plasma-cell differentiation. However, the modest increase in XBP1 mRNA in the presence of BLIMP1 indicates that other pathways are also likely to activate XBP1 transcription during plasmacytic differentiation. Therefore, BLIMP1 promotes plasmacytic differentiation by switching off genes that are required for mature B-cell function and switching on plasma-cell genes.

The downregulation of expression of BCL6 by BLIMP1 is consistent with earlier work showing that BCL6 is highly expressed in germinal-centre B cells, but that it is downregulated as B cells differentiate into plasma cells. BCL6 has been shown previously to repress the transcription of BLIMP1, so Shaffer et al. conclude that a reciprocal regulatory loop might exist whereby BCL6 and BLIMP1 antagonize the expression of each other.

But, how does BCL6 repress the expression of BLIMP1 and other target genes? Work by Vasanwala and colleagues published in The Journal of Immunology has investigated the interactions between BCL6 and the BLIMP1 promoter, and has shown that BCL6 represses BLIMP1 expression by blocking the transcriptional activity of AP1 factors.