Naïve B Cells Differentiate into Highly Activated Granzyme B-Secreting B Cells in Response to Interleukin 21 and B Cell Receptor Stimulation

Human B cells have so far not been known to express the cytotoxic molecule granzyme B (GrB). Recently we found malignant B cells from patients with chronic lymphocytic leukemia, activated with interleukin 21 (IL-21), secrete high amounts of GrB. Here we demonstrate healthy human naïve B cells differentiate into GrB-secreting B cells in response to IL-21 and B cell receptor (BCR) cross-linking. After 72 hours up to 90% of viable B cells were differentiating. GrB-secreting B cells were more resistant to apoptosis than unstimulated B cells and non-viable B cells did not contain GrB, suggesting that the primary function of B-cell-derived GrB is not self-regulation. Differentiation was associated with a CD19+CD27-IgD-CD38-phenotype, increased dextran uptake and strong upregulation of molecules involved in cell adhesion (CD54), antigen-presentation (MHC class II) and co-stimulation (CD86). In summary we describe a novel differentiation pathway of naïve B cells into highly activated GrB-positive B cells in response to IL-21 and BCR stimulation. Our data indicate this differentiation serves potential interactions with target cells including antigen uptake and presentation, but not self-regulation. Our findings may have significant implications for understanding the role of B cells in immunity, and may open novel immunotherapeutic approaches.