Blimp-1-Dependent Repression of <i>Pax-5</i> Is Required for Differentiation of B Cells to Immunoglobulin M-Secreting Plasma Cells

TLDR

B-cell lineage‑specific activator protein (BSAP), encoded by Pax‑5, is essential for B‑cell commitment and development but is absent in terminally differentiated B cells. The study demonstrates a direct link between BSAP and Blimp‑1, showing that Blimp‑1 can drive plasmacytic differentiation. The authors ectopically expressed Blimp‑1 or applied a competitive inhibitor to prove that Blimp‑1 is both necessary and sufficient to repress Pax‑5 during plasmacytic differentiation of primary splenic B cells. Blimp‑1 binds and represses the Pax‑5 promoter, down‑regulating BSAP targets CD19 and J chain, is required for IgM‑secreting plasma cell differentiation, but alone does not induce XBP‑1, underscoring Pax‑5 repression as essential in the Blimp‑1‑driven plasmacytic program.

Abstract

B-cell lineage-specific activator protein (BSAP), encoded by the Pax-5 gene, is critical for B-cell lineage commitment and B-cell development but is not expressed in terminally differentiated B cells. We demonstrate a direct connection between BSAP and B-lymphocyte-induced maturation protein 1 (Blimp-1), a transcriptional repressor that is sufficient to drive plasmacytic differentiation. Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner. By ectopically expressing Blimp-1 or a competitive inhibitor of Blimp-1, we show that Blimp-1 is both necessary and sufficient to repress Pax-5 during plasmacytic differentiation of primary splenic B cells. Blimp-1-dependent repression of Pax-5 is sufficient to regulate BSAP targets CD19 and J chain and is necessary but not sufficient to induce XBP-1. We further show that repression of Pax-5 is required for Blimp-1 to drive differentiation of splenocytes to immunoglobulin M-secreting cells. Thus, repression of Pax-5 plays a critical role in the Blimp-1-dependent program of plasmacytic differentiation.