pERKing up the BLIMP in plasma cell differentiation

University of Pennsylvania School of Medicine, John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
Science Signaling (Impact Factor: 6.28). 04/2011; 4(169):pe21. DOI: 10.1126/scisignal.2001987
Source: PubMed


The intracellular pathways that induce the differentiation of naïve B cells into antibody-secreting plasma cells remain poorly defined. A new study now provides surprising evidence that the activation of extracellular signal-regulated kinase (ERK) is pivotal for inducing the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1), which is required for plasma cell differentiation. Consequently, ERK-deficient B cells were unable to generate plasma cells effectively. This is an unexpected result, because previous work has shown that ERK signaling functions chiefly to induce cell division, whereas plasma cells are considered to be nondividing, terminally differentiated cells. This finding not only reveals an important signaling pathway that underlies antibody-mediated immunity but also raises important questions about the varying roles that ERK, and perhaps other kinases, may play in different biological contexts.

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    • "Control of terminal B cell differentiation by transcription factors operates following specific timing and pace that remain only partially understood. A large number of external and internal signals and cues impact this process by influencing transcriptional cascades (Allman and Cancro, 2011). BCL6 has an antagonistic role to the plasmablast fate-determining transcription factor BLIMP1, encoded by PRDM1, in lineage determination. "
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    ABSTRACT: Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-β1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxy)methylation, and cell fate determination.
    Full-text · Article · Oct 2015 · Cell Reports
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    ABSTRACT: Mature B cell differentiation involves a well-established transcription factor cascade. However, the temporal dynamics of cell signaling pathways regulating transcription factor network and coordinating cell proliferation and differentiation remain poorly defined. To gain insight into the molecular processes and extrinsic cues required for B cell differentiation, we set up a controlled primary culture system to differentiate human naive B cells into plasma cells (PCs). We identified T cell-produced IL-2 to be critically involved in ERK1/2-triggered PC differentiation. IL-2 drove activated B cell differentiation toward PC independently of its proliferation and survival functions. Indeed, IL-2 potentiated ERK activation and subsequent BACH2 and IRF8 downregulation, sustaining BLIMP1 expression, the master regulator for PC differentiation. Inhibition of the MAPK-ERK pathway, unlike STAT5 signaling, impaired IL-2-induced PC differentiation and rescued the expression profile of BACH2 and IRF8. These results identify IL-2 as a crucial early input in mature B cell fate commitment.
    No preview · Article · May 2012 · The Journal of Immunology
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    ABSTRACT: During the month of July, Science Signaling has highlighted mechanisms by which lymphocytes of the innate and adaptive immune responses are regulated to promote effective immunity and prevent inappropriate and damaging responses. Research Articles and Perspectives in this series and the Archives focus on the mechanisms by which the functions of T cells, B cells, and natural killer cells are regulated and the therapeutic implications of understanding the regulation of these cells.
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