Activation of human B cells negatively regulates TGF-β1 production

Background: Accumulating evidence indicate that B cells can exhibit pro-or anti-inflammatory activities. Similar to interleukin (IL)-10-competent B cells, we recently showed that transforming growth factor (TGF)-beta 1-producing regulatory B cells limit the induction of autoimmune neuroinflammation in mice, making them potentially important in maintaining peripheral immune tolerance in central nervous system inflammatory demyelinating disorders such as multiple sclerosis. Methods: In this study, we compared B cell production of TGF-beta 1 and IL-10, the two most studied regulatory cytokines, and the pro-inflammatory B cell-derived IL-6 and tumor necrosis factor cytokines under basal conditions and following polyclonal stimulation with dual B cell receptor (BCR) cross-linking and Toll-like receptor (TLR) 9 engagement. Results: We showed that resting TGF-beta 1-producing B cells fall within both the naive (CD27(-)) and memory (CD27(+)) B cell compartments. We found no spontaneous B cell-derived IL-10, IL-6 or tumor necrosis factor (TNF) production. Human B cell activation with anti-Ig antibodies plus CPG-B leads to only modest IL-10 production by memory CD19(+)CD27(+) B cells while expression levels of IL-6 and TNF by both naive and memory B cells were strongly induced. Remarkably, stimulated B cells showed significantly reduced capacity to produce TGF-beta 1. Conclusions: These findings indicate that B cell activation may facilitate the development of excessive immune responses and autoimmunity by restricting B cell-derived TGF-beta 1 production by resting B cells and favoring in turns the proinflammatory actions of activated cytokine-producing B cells.