Plasma-cell differentiation requires Blimp1

Although the transcriptional repressor B-lymphocyte-induced maturation protein 1 (Blimp1) has been previously shown to induce B-cell differentiation into immunoglobulin-producing plasma cells, until now, it has not been identified as non-redundant and essential for this process.

Mice lacking the gene encoding Blimp1, Prdm1, die in utero, so to study the dependence of B-cell differentiation and function on Blimp1, Shapiro-Shelef et al. generated mice in which Prdm1 was specifically eliminated in mature B cells, Prdm1^flox/floxCD19^cre/⁺ mice. B-cell development was normal in these animals but serum immunoglobulin was markedly reduced, even in unimmunized mice.

After immunization with either a thymus-independent (TI) or thymus-dependent (TD) antigen the immunoglobulin response generated in Prdm1^flox/floxCD19^cre/+ mice was substantially diminished when compared with control animals, as was immunoglobulin secretion after re-challenge with TD antigen. This decrease in immunoglobulin production correlated with a marked reduction in the number of antigen-specific immunoglobulin-secreting cells and consistent with this, few plasma cells or pre-plasma memory B cells could be detected in Prdm1^flox/floxCD19^cre/+ mice after either primary or secondary exposure to TD antigen. So, Blimp1 is required for the development of both plasma cells and pre-plasma memory B cells during both a primary and memory response.

To investigate the mechanisms by which Blimp1 regulates immunoglobulin secretion and plasma-cell differentiation, Shapiro-Shelef et al. analysed Blimp1-deficient B cells that were exposed to lipopolysaccharide (LPS) ex vivo. In the absence of Blimp1, switching from the membrane-associated form of the immunoglobulin heavy chain (µM) to the secreted form (µS) was markedly impaired, as was the induction of µS messenger RNA. In addition, the transcription factor X-box binding protein 1 (XBP1) was not induced by LPS stimulation of Prdm1 B cells, identifying it as a downstream target of Blimp1. However, retrovirus-mediated overexpression of XBP1 by Blimp1-deficient B cells was insufficient to rescue plasma-cell development, indicating that Blimp1 must target many factors to induce plasma-cell differentiation.

These studies using a conditional gene-deletion strategy define Blimp1 as essential for the differentiation of plasma cells and immunoglobulin secretion, and indicate that this transcription factor also has a key role in pre-plasma memory B-cell development.