Viral Antigens Trigger Granzyme B Secretion By Human Cd5+B1 Cells In The Presence Of Interleukin 21

Abstract Abstract 4729 CD5+ B1 cells are thought to play a key role in innate immune responses by producing and secreting natural immunoglobulins, which bind to a wide range of bacterial, viral antigens as well as auto-antigens. Here we demonstrate that B1 cells from human cord blood are able to express the pro-apoptotic serine protease granzyme B (GrB) in response to viruses including tick-borne encephalitis virus, rabies virus, and hepatitis B virus. Using pharmacological tools we reveal that this response depends on B cell receptor stimulation, toll-like receptor 9 engagement and interleukin 21 (IL-21), a cytokine primarily found in the acute phase of viral infections. While up to 35% of freshly isolated B1 cells directly respond with GrB expression to stimulation with inactivated viruses in the presence of IL-21, similar, though lower reactions in CD5- B2 cells are only found after, but not before vaccination of the donor against the respective virus. Of note, GrB-expressing B1 cells feature a homogeneous CD19+CD5+GrB+CD20+CD27-CD38-IgD- phenotype and B1 cell-derived GrB is secreted in an enzymatically active state, reaching levels comparable to those secreted by activated cytotoxic cells. GrB induction requires activation of similar signaling pathways as in CTL and NK cells including members of the JAK/STAT pathway. Our findings suggest GrB secretion by B1 cells represents a novel innate immune response mechanism. GrB-secreting B1 cells may play a role in early anti-viral immune defense, and may contribute to elevated serum GrB levels found in various viral diseases. Further studies will elucidate whether CD5+ B1 cells, possibly in co-operation with NK cells, exhibit cytotoxicity towards virus-infected as well as tumor cells. Disclosures: No relevant conflicts of interest to declare.