Abstract
In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves a major transcriptional switch that promotes a halt in cell proliferation and the production of secreted immunoglobulins. Here we show that the CCCTC-binding factor (CTCF) is required for the GC reaction in vivo, whereas in vitro the requirement for CTCF is not universal and instead depends on the pathways used for B-cell activation. CTCF maintains the GC transcriptional programme, allows a high proliferation rate, and represses the expression of Blimp-1, the master regulator of PC differentiation. Restoration of Blimp-1 levels partially rescues the proliferation defect of CTCF-deficient B cells. Thus, our data reveal an essential function of CTCF in maintaining the GC transcriptional programme and preventing premature PC differentiation.
Highlights
In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC)
In CTCFfl/fl; activation-induced deaminase (AID)-CRETG/ þ mice the expression of CRE and the deletion of CCCTC-binding factor (CTCF) is triggered by the expression of AID— expressed in GC B cells—and surface expression of human CD2 molecule (hCD2) can be used to track GC B cells and CTCF depletion (Supplementary Fig. 1b)
Analysis of B-cell differentiation in bone marrow and spleen did not show any difference between CTCFfl/fl; AID-CRETG/ þ and CTCFfl/ þ ; AID-CRETG/ þ mice (Supplementary Fig. 1c–e and Supplementary Table 1), indicating that B-cell differentiation is not affected before GC formation in CTCFfl/fl; AID-CRETG/ þ mice
Summary
In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). CTCF maintains the GC transcriptional programme, allows a high proliferation rate, and represses the expression of Blimp-1, the master regulator of PC differentiation. Proliferating GC B cells engage in the somatic remodelling of immunoglobulin (Ig) genes by somatic hypermutation, which introduces mutations in the variable region of the immunoglobulin genes and generates clonally related B cells expressing immunoglobulins with slightly altered binding specificities[1,3]. Blimp-1 acts as a transcriptional repressor that promotes B-cell proliferation arrest, establishes the PC transcriptional programme and triggers immunoglobulin secretion[7,8,9,10]. The function of CTCF in mature B cells, and during the GC reaction, is unclear
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