IRF4 Deficiency Leads to Altered BCR Signalling Revealed by Enhanced PI3K Pathway, Decreased SHIP Expression and Defected Cytoskeletal Responses

The graded expression of transcription factor interferon regulatory factor 4 ( IRF 4) regulates B cell development and is critical for plasma cell differentiation. However, the mechanisms, by which IRF 4 elicits its crucial tasks, are largely unknown. To characterize the molecular targets of IRF 4 in B cells, we established an IRF 4‐deficient DT 40 B cell line. We found that in the absence of IRF 4, the expression of several molecules involved in BCR signalling was altered. For example, the expression of B cell adaptor for PI3K ( BCAP ) was upregulated, whereas the SHIP (SH2‐containing Inositol 5?‐Phosphatase) expression was downregulated. These molecular unbalances were accompanied by increased BCR ‐induced calcium signalling, attenuated B cell linker protein ( BLNK ) and ERK activity and enhanced activity of PI3K/protein kinase B (Akt) pathway. Further, the IRF 4‐deficient cells showed dramatically diminished cytoskeletal responses to anti‐IgM cross‐linking. Our results show that IRF 4 has an important role in the regulation of BCR signalling and help to shed light on the molecular mechanisms of B cell development and germinal centre response.