Interferon-λ Enhances the Differentiation of Naive B Cells into Plasmablasts via the mTORC1 Pathway

Type III interferon (interferon lambda [IFN-lambda]) 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-lambda. Using B cell transcriptome profiling, we investigate the immune-modulatory role of IFN-lambda in B cells. We find that IFN-lambda-induced gene expression in B cells is steady, prolonged, and importantly, cell type specific. Furthermore, IFN-lambda enhances the mTORC1 (mammalian/mechanistic target of rapamycin complex 1) pathway in B cells activated by the B cell receptor (BCR/anti-IgM). Engagement of mTORC1 by BCR and IFN-lambda induces cell-cycle progress in B cells. Subsequently, IFN-lambda boosts the differentiation of naive B cells into plasmablasts upon activation, and the cells gain effector functions such as cytokine release (IL-6 and IL-10) and antibody production. Our study shows how IFN-lambda systematically boosts the differentiation of naive B cells into plasmablasts by enhancing the mTORC1 pathway and cell-cycle progression in activated B cells.