Molecular Mechanisms Driving IL-10- Producing B Cells Functions: STAT3 and c-MAF as Underestimated Central Key Regulators?

Abstract

Regulatory B cells (Bregs) have been highlighted in very different pathology settings including autoimmune diseases, allergy, graft rejection, and cancer. Improving tools for the characterization of Bregs has become the main objective especially in humans. Transitional, mature B cells and plasma cells can differentiate into IL-10 producing Bregs in both mice and humans, suggesting that Bregs are not derived from unique precursors but may arise from different competent progenitors at unrestricted development stages. Moreover, in addition to IL-10 production, regulatory B cells used a broad range of suppressing mechanisms to modulate the immune response. Although Bregs have been consistently described in the literature, only a few reports described the molecular aspects that control the acquisition of the regulatory function. In this manuscript, we detailed the latest reports describing the control of IL-10, TGFβ, and GZMB production in different Breg subsets at the molecular level. We focused on the understanding of the role of the transcription factors STAT3 and c-MAF in controlling IL-10 production in murine and human B cells and how these factors may represent an important crossroad of several key drivers of the Breg response. Finally, we provided original data supporting the evidence that MAF is expressed in human IL-10- producing plasmablast and could be induced in vitro following different stimulation cocktails. At steady state, we reported that MAF is expressed in specific human B-cell tonsillar subsets including the IgD+ CD27+ unswitched population, germinal center cells and plasmablast.

A computational approach for deciphering the interactions between proximal and distal regulators in B cell differentiation

“…To validate the inferred TFBS activities, we compared the publicly available peak positions of three TFs in GCB cells; BACH2 and MAFK binding to the TFBS MAF (44), and MYC binding to the TFBS Ebox (45). Although the MAF was detected with negative RCs (Figure 4A), consistent with the repressive activities of BACH2 and MAFK (42), most of the DDGs possessed the TF peaks at LRCs (Figure 4B). Interestingly, simultaneous peak presence at the promoters and LRCs was associated with gene suppression.…”

“…Our regression models successfully identified well-documented transcriptional cis -regulators, such as the TFBSs Bcl-6, AP-1, Blimp-1, Bach2, and XBP1 (6,42,43), along with the diverse TFBS activities, according to their locations and target genes (Figure 4A, Figure S2C). For instance, in the model predicting NB-DUG expression, Bcl-6 and Blimp-1 were identified in the promoter regions, while STAT1 and AP-1 originated from LRCs.…”

Selective Inhibitors of Janus Kinase 3 Modify Responses to Lipopolysaccharides by Increasing the Interleukin-10-to-Tumor Necrosis Factor α Ratio

“…IL-10 can be induced in macrophages by interferon/STAT1 signaling, which itself is inducible by LPS stimulus . As IL-10 induces both transcription of its own mRNA ( via STAT3) and its negative regulator SOCS1, − the overall effects on IL-10 levels are complex and depend on factors like time and cell type. Nonetheless, these data show that isolated cell types exposed to high concentrations of substance in vitro exhibit responses that differ from the in vivo setting.…”

The HMGB1 (C106A) mutation inhibits IL-10-producing CD19hiFcγRIIbhi B cell expansion by suppressing STAT3 activation in mice

“…The mechanisms underlying Bregs differentiation are unclear but involve transcription factors such as IRF4 ( 31 ), STAT3 ( 26 ), and c-MAF ( 32 ). Moreover, extracellular HMGB1 activates the STAT3 signaling pathway ( 33 ) and intracellular HMGB1 binds to STAT3 ( 34 ).…”