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.
Highlights
B cells with immunosuppressive function (Bregs) have been highlighted for the first time in the murine experimental autoimmune encephalomyelitis (EAE) model [1]
We described the last reports establishing new insights into the molecular control of transforming growth factor (TGF) b, granzyme B (GZMB), and IL-10 producing B cells (B10) with a specific focus of an understudied transcription factor (TF) in B cells: the avian musculoaponeurotic fibrosarcoma oncogene c-MAF (MAF)
We previously demonstrated that the CD5 molecule, overexpressed in chronic lymphocytic leukemia (CLL) B cells, promoted IL-10 expression and cell survival through a STAT3 and NFAT2-dependent pathway [82] and that IL-10 expression by B cells was directly connected with the aggressivity of the disease [83]
Summary
B cells with immunosuppressive function (Bregs) have been highlighted for the first time in the murine experimental autoimmune encephalomyelitis (EAE) model [1]. The heterogeneity of the Breg subsets is a subject of interest for many years [2–5] and consensus opinions suggest that Bregs may arise from multiple progenitors depending on the microenvironment. Beyond their phenotypic status, Bregs used different immunosuppressive mechanisms such as the production of interleukin (IL)-10, granzyme B (GZMB), and transforming growth factor (TGF) b to regulate other immune cells [3, 6, 7]. New studies are starting to clarify the different molecular mechanisms that may control the acquisition of the Breg function. We described the last reports establishing new insights into the molecular control of TGF b, GZMB, and IL-10 producing B cells (B10) with a specific focus of an understudied transcription factor (TF) in B cells: the avian musculoaponeurotic fibrosarcoma oncogene c-MAF (MAF)
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