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Viral Antigens Trigger Granzyme B Secretion by Human CD5+ B1 Cells in the Presence of Interleukin 21

CD5+ B1 cells are thought to play a key role in innate immune responses by secreting natural immunoglobulins. Here we demonstrate that human B1 cells (B1C) are able to express the pro‐apoptotic serine protease granzyme B (GzmB) in response to viruses including tick‐borne encephalitis, rabies and hepatitis B virus. We reveal that this response depends on B1C receptor stimulation, TLR9 engagement and interleukin 21 (IL‐21), a cytokine primarily found in the acute phase of viral infections. Up to 35% of freshly isolated B1C directly respond with GzmB expression to stimulation with inactivated viruses in the presence of IL‐21. Of note, GzmB is secreted by B1C in an enzymatically active state, reaching levels comparable to those secreted by cytotoxic cells and its induction requires activation of similar signaling pathways as in CTL and NK cells. Our findings suggest GzmB secretion by B1C represents a novel innate immune response mechanism. GzmB‐secreting B1C may play a role in the early anti‐viral immune defense, and may contribute to elevated serum GzmB levels found in viral diseases. Further studies will elucidate whether B1C cells exhibit cytotoxicity towards virus‐infected or tumor cells.