Interferon-? enhances the differentiation of naïve B-cells into plasmablasts via mTORC1 pathway

Type III interferon (IFN-?) is known to be a potential immune modulator, but the mechanisms behind its immune-modulatory functions and its impact on plasmablast differentiation in humans, remain unknown. Human B-cells and their subtypes directly respond to IFN-?. We performed B-cell transcriptome profiling to investigate the immune-modulatory role of IFN-? in B-cells. We found that IFN-? induced gene expression in B cells is steady, prolonged and importantly cell type-specific. Further, IFN-? enhances the mTORC1 (mammalian/mechanistic target 34 of rapamycin complex 1) pathway in the B-cell receptor-activated B-cells (BCR/anti-IgM). The engagement of mTORC1 by BCR and IFN-lambda induces the cell cycle progress in B-cells. Subsequently, IFN-? boosts the differentiation of naïve B-cells into plasmablast upon activation and the cells gain effector functions such as cytokine release (IL-6, IL-10) and antibody production. Our study shows how IFN-? systematically boosts the differentiation of naïve B-cells into plasmablasts by enhancing the mTORC1 pathway and cell cycle progression in activated B-cells, which is a previously unknown immune modulatory role of IFN-?. Overall design: mRNA profiles of isolated B cells stimulated with IFN-lambda (4 donors) or IgM (6 donors) or with a combination of IgM and IFN lambda (6 donors). Unstimulated B-cells from 5 donors were used as control.