Figure 2. The ‘checks and balances’ system of human PC differentiation.

T-cell dependent (TD) activation of Ag-specific B cells leads to formation of germinal centers (GCs) in lymphoid organs. Several transcription factors are maintained or upregulated in GC B cells to allow affinity maturation to take place, i.e. inhibiting the differentiation of GC B cells into PCs by direct repression of the transcription of factors that are required for PC formation [29,30]. Consequently, expression levels of these repressors must decrease to allow the differentiation of GC B cells once B cell selection is successfully achieved. Once expressed, PC factors repress the factors required for B cell identity and GC phenotype. Also, PC factors can induced their own and each others expression, in order to fully establish the PC phenotype. Research with human B cell systems has confirmed and extended the factors involved in the GC repression network established in murine studies. In the figure, protein expression and repression mechanism that are confirmed or discovered in human systems are displayed in black, results from mouse studies only are displayed in grey. For human B cells it was shown that BCL6 is highly expressed in GC center B cells [5] and represses BLIMP1 [39] as well as STAT3 [41]. PAX-5 and Spi-B are expressed in naïve, memory and activated human B cells [5,42] and repress BLIMP1 and XBP-1 in activated GC B cells [42,49]. BLIMP1 and IRF-4 levels are high in human plasmablasts and PCs [5,37]. IL-21 secreted by Tfh induces BLIMP1 in a STAT3-dependent manner [33]. BCR Ag stimulation induces phosphorylation and degradation of BCL6 [107], while CD40 triggering results in downregulation of BCL6 expression [108], suggesting a role for Ag and T cell help in GC differentiation by modulating BCL6 levels. CD25⁺ GC B cells express high levels of pSTAT5, a direct inducer of BCL6, resulting in memory differentiation [39]. BCL6 may or may not be required for the differentiation of memory B cells in the GC [60].