B cells belong to the acquired immune system and play an important role for the humoral immune response. In recent years several hints emerged indicating that B cells may exhibit additional immune functions beyond antibody production. Lately we demonstrated that B cells are able to produce granzyme B (GrB) after stimulation with Interleukin(IL)-21 and antibodies against the B cell receptor. GrB is a serine protease, classically known to be produced by cytotoxic T cells for the induction of

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... osis such as in virus-infected cells. In the meantime, several additional GrB substrates have been identified. Previously, it was shown that regulatory T cells (Treg) and plasmacytoid dendritic cells are able to modulate cellular immune responses in a GrB-dependent way. Therefore we hypothesized, that GrB-secreting B cells might also exhibit regulatory functions. Here we showed that B cells produce GrB after coincubation with Cluster of Differentiation(CD)4+ T cells. This effect is highly dependent on IL-21, secreted by these T cells. Furthermore we demonstrated that proliferation but not the survival of CD4+ T cells was suppressed by GrB-secreting B cells. We demonstrated that B cells directly transfer active GrB to T cells and therefore hypothesized that GrB may block part of the T cell receptor (TCR) signaling pathway. Indeed, we found that B cell-derived GrB can degrade the zeta-chain of activated T cells, which is a known GrB substrate. Furthermore we analyzed surface markers of GrB-secreting B cells and found CD25 to be upregulated. Interestingly, this high affinity part of the IL-2-receptor is also expressed at high levels on Treg. It was therefore discussed earlier whether or not one reason for the suppressive effects of Treg might be deprivation of IL-2 in the environment of bystander T cells. In conclusion, our findings suggest that GrB-secreting B cells may have regulatory functions in the human immune system with IL-21 being a key cytokine for their induction.