Specific Induction of Granzyme B in Human B Cells by Viral Antigens.

B cells are not currently known to produce granzyme B (GrB) in (patho-) physiological settings. We recently reported that B-chronic lymphocytic leukemia cells and normal B cells treated with interleukin-21 (IL-21) and anti-B cell receptor antibodies (anti-BCR) produce functional GrB. Here we demonstrate for the first time that viral antigens can also induce specific peripheral B lymphocytes to produce and secrete substantial amounts of active GrB. Using FACS, ELISpot, immunofluoresence and western blot we show that B cells from subjects recently vaccinated against tick-borne encephalitis virus (TBEV) but not unvaccinated subjects respond to viral TBEV antigens with GrB secretion in a dosedependent manner. This response is direct and occurs only in the presence of co-activation with certain IL-2 family cytokines such as IL-21. Similar results were found with other viruses including hepatitis B and rabies. GrB production in B cells required activation of JAK1 and STAT3 and inhibition of JAK1 by pyridone 6 completely abrogated GrB induction by viral antigens or anti-BCR. Our findings suggest GrB secretion by B cells may be part of a novel, anti-viral immune response mechanism. Further studies will elucidate whether or not granzyme B-secreting B cells can act as cytotoxic cells towards virus-infected cells.