CD40 signaling can block the function of BCL6 through 2 independent mechanisms. (A) In dark zone centroblasts, BCL6 represses target genes through recruitment of the SMRT and N-CoR corepressors, both of which form histone deacetylase (HDAC) complexes. This facilitates proliferation and immunoglobulin affinity maturation. (B) CD40 signaling in the light zone, for example, by GC T cells, leads to posttranslational modification of these corepressors () and loss of their association with BCL6. This leads to a failure to maintain silencing of these genes, which can now become reactivated even in the presence of BCL6. The double arrow between dark zone and light zone indicates that this is a reversible mechanism. This mechanism is rapid and may allow damaged B cells to be removed from the GC reaction. (C) In the second mechanism, sustained CD40 signaling, for example, by follicular dendritic cells, can activate NFκB, which in turn induces expression of IRF4, which can then directly repress BCL6 mRNA expression leading to down-regulation of BCL6 and up-regulation of its target genes. This mechanism is slower but is irreversible and leads to differentiation of B cells positively selected for high-affinity antibody.