Transcriptional control of Complement Receptor 2: significance to B cell biology and autoimmunity

[Truncated] Complement receptor 2 (CR2) expressed primarily on the cell surface of B cells and follicular dendritic cells, is the receptor for cleaved complement C3 fragments. At the B cell surface, CR2 forms the ligand binding domain of the co-receptor complex for the B cell receptor which functions in part, to lower the threshold for B cell activation in the presence of low avidity ligands. CR2 expression on B cells is stringently regulated such that expression is limited to the surface of mature B cells. The appropriate timing of CR2 expression during B cell development, and the level of CR2 expression, are critical to the development of a healthy B cell repertoire. Significant evidence from both murine models and human patients demonstrates that CR2 is a susceptibility gene for the autoimmune condition systemic lupus erythematosus (SLE). However, the contribution of CR2 to the development or exacerbation of human autoimmune disease is poorly understood.

The expression of CR2 is primarily regulated at the level of transcription, and a number of transcriptional control regions in the CR2 proximal promoter and first intron have been described. However, the transcriptional mechanisms driving up-regulation of CR2 expression precisely concurrent with B cell maturation remain to be elucidated. Further, up-regulation of CR2 during this window coincides with a critical checkpoint for autoreactivity and has been associated with facilitating escape from negative selection. Therefore, the focus of this research was to characterise core promoter elements regulating transcription initiation and investigate the potential signalling mechanisms driving CR2 expression. To this end, we utilised cell-line models blocked at the pre-B, mature B and terminally differentiated B cell stages. We show that in mature B cells CR2 transcription proceeds from a focused transcriptional start site regulated by a nonconsensus TATA box, an initiator element and a downstream promoter element. Furthermore, occupancy of the general transcriptional machinery in pre-B versus mature B cell lines correlates with CR2 expression level and points to a sharp transition between inactive and active states during this developmental window.