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Developmentally regulated expression of MEF2C limits the response to BCR engagement in transitional B cells

Transitional and naïve mature peripheral B cells respond very differently to B‐cell receptor (BCR) cross‐linking. While transitional B cells undergo apoptosis upon BCR engagement, mature B cells survive and proliferate. This differential response correlates with the capacity of mature, but not transitional B cells to transcribe genes that promote cell survival and proliferation, including those encoding c‐Myc and the Bcl‐2 family members Bcl‐xL and A1. We recently demonstrated that transitional B cells fail to assemble transcriptional machinery at the promoter region of these target genes despite equivalent cytoplasmic signaling and nuclear translocation of key transcription factors including NF‐κB and nuclear factor of activated T cells (NFAT). The transcription factor myocyte enhancer factor‐2C (MEF2C) is regulated by both calcineurin and mitogen‐activated protein kinase signaling pathways, and is essential for proliferation and survival downstream of BCR engagement in mature B cells. In this work, we demonstrate that transitional B cells have intrinsically low levels of MEF2C protein and DNA‐binding activity, and that this developmental difference in MEF2C expression is functionally significant. Forced expression of MEF2C in transitional B cells promoted cell survival, proliferation, and upregulation of pro‐survival genes. Thus, low MEF2C expression limits transitional B‐cell responsiveness to BCR engagement before these cells reach maturity.