Inflammasome functional activities in B lymphocytes.

Studies in animal models and human subjects have shown that, in addition to their implication in innate immunity, inflammasomes also can play a role in adaptive immunity. However, the contribution of the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway to adaptive immunity remains incompletely explored. Here, we show that NLRP3 plays an important role in different facets of B cell functions, including proliferation, antibody production, and secretion of inflammatory and anti-inflammatory cytokines. When exposed to B cell receptor engagement, Toll-like receptor activation, stimulation in conditions that mimic T cell-dependent responses, or NLRP3 activation, B cells manifest disparate responses and produce different cytokine patterns critical for modulating innate and adaptive immunity, indicating that the cytokines produced serve a critical link between the early innate immune response and the delayed adaptive immunity. Importantly, genetic ablation of nlrp3 reduced the inflammasome-mediated functions of B cells. We propose that, in the absence of other cell types, the potential of B lymphocytes to respond to NLRP3 engagement enables them to initiate inflammatory cascades through recruitment of other cell subsets, such as macrophages and neutrophils. Since NLRP3 activation of B cells is not followed by pyroptosis, even in the presence of a basal caspase-1 activity, this pathway acts as a bridge that optimizes interactions between the innate and adoptive branches of the immune response.

DNA methylation trajectories during innate and adaptive immune responses of human B lymphocytes.

B lymphocytes can engage in either a rapid T cell-independent pathway (TI) or a delayed long-lasting T cell-independent (TD) response through highly ordered transcriptional programs, yet the detailed underlying mechanisms are unclear. Since DNA methylation plays a key role in controlling gene expression and lineage specification, we explored the dynamics of whole-genome cytosine modifications during the ex vivo response of human B cells isolated from normal individuals by negative selection. We found that B cell differentiation following TI and TD signalling is accompanied by extensive remodelling of the epigenome, including global gain and loss of DNA methylation. The epigenetic changes map to different regions of the B cell genome, including non- C-phosphate-G CpG islands, indicating that modifications of distal regulatory elements likely regulate specific gene transcription in B cells. Non-CpG methylation also occurs in differentiating human B cells, suggesting that this DNA modification is involved in transcriptional regulation of B cell genes with promoters exhibiting a low-density methylation, possibly by changing the chromatin shape that could have an impact on gene expression. Most strikingly, compared to TD activation, stimulation of B cells through an innate pathway induced higher levels of DNA methylation modifications at CpG, CHG and CGG contexts, supporting the view that DNA methylation modifications are used in distinct trajectories to specify the TI and TD B lymphocyte responses.