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Pair of Papers Highlights Role of Blimp-1 in Immune Plasma Cell Development, Function

NEW YORK (GenomeWeb) – The protein Blimp-1 plays a key role in the development and function of immune plasma cells, according to two studies appearing in Nature Immunology today.

Two teams, one from Austria and the other from Australia, found that Blimp-1 regulates the development of plasma cells from precursor B cells and that the transcription factor is further needed for mature plasma cells to function properly.

"Most of the essential functions of plasma cells are controlled by the factor Blimp-1," Meinrad Busslinger, an investigator from the Research Institute of Molecular Pathology in Vienna and an author on both papers, said in a statement. "It regulates their mobility and migration to the bone marrow. … Humoral immunity would not be possible without Blimp-1."

Plasma cells are white blood cells that develop from B-cells that have been activated by antigens. They form plasmablasts that reside in the bone marrow for years or even decades and provide long-term protection through antibody-mediated immunity.

Using RNA-sequencing, Busslinger and his Austrian colleagues compared pre-plasmablasts that were either deficient or Blimp-1 or had sufficient levels of the protein. Blimp-1, they found, controls some 40 percent of the gene expression changes that take place during the B cell-to-plasmablast transition, according to their Nature Immunology report.

In particular, it activated 245 of the 648 upregulated genes during plasmablast differentiation and repressed 173 of the 424 downregulated genes during plasmablast differentiation.

This suggests Blimp-1 plays a crucial role in plasma cells, said first author Martina Minnich, also from IMP.

Repressed Blimp-1 target genes include 32 signal transducers, 16 cell-surface receptors, and 13 transcriptional regulators. In particular, she and her colleagues noted that it repressed Aicda, which encodes the cytidine deaminase AID, to lead to the silencing of B cell-specific gene expression, antigen presentation, and class-switch recombination in plasmablasts.

Meanwhile, activated Blimp-1 target genes include 15 signal transducers, seven cell-surface receptors, and seven transcriptional regulators. In addition, the researchers uncovered nine activated target genes and 21 repressed target genes encoding cell-surface proteins, signal transducers, and cytoskeletal proteins that are all involved in cell adhesion and migration. This, they added, indicated Blimp-1 controls plasmablasts' migratory and sessile behavior.

It also activated genes that lead to increased expression of the plasma cell regulator IRF4 as well as proteins involved in the secretion of immunoglobulin.

While Blimp-1 is a key part of plasma cell development, the Walter and Eliza Hall Institute of Medical Research-led team noted that it is not essential for the survival of plasma cells, as IRF4 is. However, as they reported in their paper today, Blimp-1-deficient plasma cells lose their ability to secrete antibodies.

By removing Blimp-1, IRF4, or XBP-1 — all of which are involved the differentiation of activated B cells into plasma cells — from mature plasma cells, the researchers found that IRF4 was needed for plasma cell survival, though Blimp-1 and XBP-1 were not.

Through RNA-seq of plasma cells with active or inactive Blimp-1, the researchers found that Blimp-1 isn't needed to maintain plasma cell identity, despite its role in the development of plasma cells. While it does appear to continue to repress B-cell genes and transcription, the researchers suggested that the plasma cell transcriptome, once established by Blimp-1, could be maintained independently of it.

In addition, by examining immunoglobulin secretion in mice with or without Blimp-1 in their plasma cells, they found that Blimp-1 has a crucial role in the production of immunoglobulin-encoding transcripts, which they noted, allows plasma cells to produce large amounts of antibodies.

"[Our study has] demonstrated that while the survival and identity of long-lived [plasma cells] is largely independent of Blimp-1, this multifunctional transcriptional regulator is essential for the molecular and cellular changes that support the extremely high and sustained rates of antibody secretion that are essential for protective immunity," the researchers wrote.

While these studies shed light on how the immune system works, it also could help researchers understand when it goes awry, according to the IMP. Mutations in Blimp-1, for instance can prevent B-cell differentiation and lead to the development of lymphoma.