CD40 Ligand Determines Whether Interleukin 21 Induces Differentiation of Human B Cells Into Plasma Cells or Into Granzyme B-Secreting Cytotoxic Cells.

Abstract 2675

Poster Board II-651

Interleukin 21 (IL-21) is a novel and highly promising cytokine for the treatment of neoplastic and infectious diseases. Recently, IL-21 has been identified as inducer of plasma cell differentiation. Here we show that CD40 ligand is critically involved in this process and that, in its absence, human B cells differentiate into granzyme B (GzmB)-secreting cytotoxic cells rather than plasma cells. GzmB expression and secretion by human B cells was demonstrated by FACS analysis, ELISpot, ELISA, Sensizyme, Western immunoblotting, RT-PCR, and spinning disk confocal microscopy. GzmB secretion requires the presence of IL-21 and B cell receptor engagement, and depends on phosphorylation of JAK1/3 and STAT3. CD40 ligation effectively suppresses GzmB secretion by B cells, suggesting GrB-secreting B cells play a role in the early phase of inflammatory processes, before CD40 ligand-expressing T cells are present. Of note, ex-vivo re-stimulation of B cells from recently vaccinated individuals with inactivated viruses also induces GzmB expression. GzmB is enzymatically active and GzmB-secreting B cells induce apoptosis in various tumor cell lines, a process we were able to visualize by using spinning disk confocal microscopy. Our data reveal an as yet unrecognized role of IL-21-activated B cells, which involves GzmB secretion and cellular cytotoxicity. Our findings may have implications for the understanding of tumor immunosurveillance and early anti-viral immune responses, and may open novel approaches for the immunotherapy of neoplastic and viral diseases.