Roadmap to a plasma cell: Epigenetic and transcriptional cues that guide B cell differentiation

Abstract

B cell differentiation is a multistep process that ultimately leads to the formation of plasma cells or antibody-secreting cells (ASCs), a specialized cell type that functions as an antibody factory. Once initiated, B cell differentiation encompasses multiple transitory cell types that allow for amplification of responding cells and diversification of the antibody repertoire as well as cell fate endpoints such as antigen-experienced memory and short-and long-lived ASC. Aided by the adoption of genomic profiling techniques that are rapidly improving in sensitivity, it is now possible to profile the molecular changes that occur in rare transitory B cell differentiation stages and patient samples where cells are limiting. In this review, we will discuss how cell division influences the transcriptome, transcription factor networks, and epigenetic programs that are remodeled during B cell differentiation, and provide a generalized roadmap for ASC differentiation.

Epigenetic gene regulation in plasma cells

“…Although there are differences in the cell types that emerge and timing of TI and TD B cell responses, few transcriptional differences in SLPC or LLPC have been identified, suggesting that the processes that lead to ASC formation are likely similar 7,97,98 . Indeed, SLPCs contribute to early protective antibodies to influenza, 99 and more recent work demonstrated that extrafollicular responses correlated with early neutralizing antibodies in critically ill COVID‐19 patients 100 .…”

A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation

“…Plasma cell differentiation requires profound transcriptional and epigenetic reprogramming and is linked to cell division ( 7 ). On the one hand, transcriptional reprogramming is accomplished through the interplay of opposing transcriptional networks: PAX5, BCL6, BACH2 and low levels of IRF4 govern B cell and GC B cell fates whereas high levels of IRF4, BLIMP1 and XBP1 dictate the plasma cell program.…”

“…Through repression of each other’s expression, the latter gain functional dominance over the former during plasma cell differentiation ( 8 , 9 ). On the other hand, epigenetic reprogramming comprises DNA methylation/and demethylation, histone modification and chromatin remodeling, which ultimately determine gene expression and thereby have important roles in plasma cell differentiation ( 7 ). However, the mechanisms by which epigenetic factors regulate plasma cell differentiation are largely unknown.…”

Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis

“…In the latter case, B cells relocate to the follicle center to undergo expansion and affinity maturation to produce high-affinity long-lived PC and memory B cells. The magnitude and duration of the EF and GC responses rely on signals from the microenvironment [8], epigenetic and transcriptional cues [9] as well as on metabolic reprogramming [10]. In the CLP model, impaired GC formation results in a reduced antigen-specific antibody response [2,3,11].…”