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

• Published in: Scandinavian journal of immunology 2015-11, Vol.82 (5), p.418-428
• Main Authors: Budzyńska, P. M., Niemelä, M., Sarapulov, A.V., Kyläniemi, M.K., Nera, K.‐P., Junttila, S., Laiho, A., Mattila, P.K., Alinikula, J., Lassila, O.
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Avian Proteins - genetics; Avian Proteins - metabolism; B-Lymphocytes - physiology; Calcium Signaling - genetics; Cell Line; Chickens; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation - genetics; Gene Knockout Techniques; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Oncogene Protein v-akt - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation - genetics; Protein-Tyrosine Kinases - metabolism; Receptors, Antigen, B-Cell - metabolism; Syk Kinase
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/sji.12343

The graded expression of transcription factor interferon regulatory factor 4 (IRF4) regulates B cell development and is critical for plasma cell differentiation. However, the mechanisms, by which IRF4 elicits its crucial tasks, are largely unknown. To characterize the molecular targets of IRF4 in B cells, we established an IRF4‐deficient DT40 B cell line. We found that in the absence of IRF4, 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 IRF4‐deficient cells showed dramatically diminished cytoskeletal responses to anti‐IgM cross‐linking. Our results show that IRF4 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.