Background/Purpose: The efficacy of B-cell depletion therapy highlights a pathogenic role of B cells in autoimmune diseases. In certain conditions, elimination of B cells can lead to exacerbation of these diseases, suggesting the existence of regulatory B cells (Bregs). Bregs are often referred to as IL-10-producing B cells, however it is possible that Bregs can exert a regulatory function by an IL-10-independent mechanism. Granzyme B (GzmB) is known to exert both cytotoxic and non-cytotoxic effects on various cell types. In this study, we have determined whether granzyme B (GzmB)-producing B cells could function as another type of Bregs in humans, and also have tested their functions in patients with systemic lupus erythematosus.

Methods: Levels of GzmB mRNA and protein in B cells were assessed using quantitative real-time PCR and intracellular staining, respectively. To evaluate the function of GzmB-producting B cells, they were co-cultured with activated T cells, and growth, survival and cytokine production of T cells were then assessed using flow cytometry.  

Results: Among the stimulators tested, IL-21 was the potent inducer of GzmB in normal B cells and it acted synergistically with antigen receptor stimulation. Naive B cells produced higher levels of GzmB as compared with memory B cells. In addition, GzmB-producing B cells inhibited the growth, survival and cytokine production of T cells, which is in line with the idea that these cells function as Bregs in normal subjects. In SLE patients, naive B cells similarly produced more GzmB than memory B cells, however levels of its production in both subsets were apparently higher than those in normal subjects. Intriguingly, however, GzmB-producing B cells in SLE patients were without regulatory effects on T cell functions. A molecular explanation for these findings is now in progress.

Conclusion: Our current findings could help to better understand a role of Bregs in the pathogenesis of autoimmune diseases as well as to provide a novel clue to manipulate the generation of Bregs for therapeutic application in the future.