Incompletely activated CD4+ T cells induce granzyme B+ regulatory B cells in an interleukin 21‐dependent manner

Immune regulation is central for the development of an efficient cellular immune response. Both Treg cells and plasmacytoid DC can suppress T cell proliferation in a granzyme B (GzmB)‐dependent manner. In the present study we found that, depending on stimulation with interleukin (IL−) 21, B cells (BC) can also express GzmB and suppress T cell proliferation. GzmB expression in BC is enhanced by BC receptor engagement, and is suppressed by CD40 ligation. Since CD4+ T cells are a main source of IL‐21, we tested whether they can induce GzmB in BC. We found that incompletely activated CD4+ T cells, but not fully activated T cells can induce GzmB in co‐cultured BC. Using confocal microscopy, we showed that BC‐derived GzmB is enzymatically active and that GzmB+ BC transfer GzmB to CD4+ T cells. Furthermore, GzmB+ BC decreased CD4+ T cell expression of the TCR‐zeta chain, a GzmB target, which is required for T cell proliferation. Our results suggest BC may regulate cellular adaptive immune responses by Treg cell‐like mechanisms. Inhibition of BC‐derived GzmB may represent a novel strategy to induce more effective and comprehensive cellular immune responses.