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

Abstract

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.