Fine tuning of IRF‐4 expression by SWAP‐70 controls the initiation of plasma cell development

The generation of plasma cells (PCs) is key for proper humoral immune responses. The transcription factors IRF‐4 and BLIMP‐1 (B‐lymphocyte induce maturation protein‐1) control PC commitment, but the underlying regulatory mechanisms are incompletely understood. Here we have identified SWAP‐70 as being critically involved in Toll‐like receptor (TLR)‐triggered PC differentiation. Upon activation through various TLRs, Swap‐70−/− B cells were activated and proliferated normally. However, expression of BLIMP‐1 was markedly reduced and PC differentiation was impaired. Four hours of LPS stimulation were sufficient to drive PC differentiation, and SWAP‐70 was required during this initial period. Swap‐70−/− B cells pre‐activated in vitro failed to efficiently differentiate into PCs upon adoptive transfer into recipient mice. Re‐introduction of SWAP‐70 into Swap‐70−/− B cells rescued their development into PCs, and SWAP‐70 over‐expression in wild‐type (WT) B cells increased PC generation. In the absence of SWAP‐70, IRF‐4 protein levels were reduced and the IRF‐4high B220+ CD138− compartment, including PC precursors, was strongly diminished. Ectopic expression of SWAP‐70 increases IRF‐4 protein levels and PC differentiation in WT and Swap‐70−/− B cells, and IRF‐4 over‐expression in Swap‐70−/− B cells elevates PC differentiation to WT levels. Thus, in a dose‐dependent manner, SWAP‐70 controls IRF‐4 protein expression and thereby regulates the initiation of PC differentiation.