In the follicular pathway, the B cells can differentiate into GC B cells: centroblasts and centrocytes. GCs are specialized structures forming in the B cell follicles that

provide an environment for antibody affinity maturation, class switching and induction of plasmacytic differentiation. The affinity maturation produces the high-affinity B cell clones by cycles of cell proliferation, somatic hypermutation (SHM) of Ig gene variable regions and selection gaining increased Ig affinity [39] (Fig. 2). The key transcriptional regulator of GC formation and function is Bcl6 (encoded by the B cell lymphoma 6 gene). Bcl6-deficient mice lack GCs and affinity matured B cells [40, 41]. On the other MAPK Inhibitor Library concentration hand, constitutive expression of Bcl6 in B cells in vivo results in increased size of GCs [42]. Within the B cell lineage, Bcl6 mRNA is observed already in pre B cells, mature B cells and GC B selleck chemicals cells but not in plasma cells [43–45]. The expression of Bcl6 protein is highly increased in GC B cells [44] with higher expression in centroblasts than in centrocytes [46]. The expression of Bcl6 in GCs is maintained for example by interleukin-21 (IL-21) [47–49] that is secreted by many cell types, particularly by follicular helper T cells (TFHs) [50,

51]. IL-21 receptor signals via STAT3 and STAT5, which promote Bcl6 expression [48, 52, 53]. Analyses of Bcl6 target genes have revealed that Bcl6 maintains the centroblast gene expression signature that includes repression of genes involved in the detection and response to DNA damage (such as p53, ATR and CHEK1) to allow physiological Mirabegron genomic instability associated with SHM and class switch recombination (CSR) while promoting cell cycle by repressing genes such as CCND2, CDKN1A and CDKN1B [39, 54, 55]. Activation-induced cytidine deaminase is absolutely needed for both SHM and CSR [56–58]. Pax5 controls the expression

of AID, as the AID gene has a binding site for Pax5 that is needed for its expression [59], and the expression of AID in DT40 B cell line depends on Pax5 expression [8]. Interestingly, re-expression of Pax5 in Bcl6-deficient DT40 cells that also undergo spontaneous plasma cell differentiation cannot support the expression of AID (J. Alinikula, K.-P. Nera, S. Junttila and O. Lassila, unpublished observations), showing that Bcl6 is also necessary to sustain SHM and CSR via regulation of AID. Bcl6 knockout mice are capable of producing plasma cells, but not efficiently the long-lived population, supporting the role of Bcl6 in promoting GC B cell functions [41, 60, 61]. Thus, Pax5 and Bcl6 co-operate to maintain the GC phenotype before the induction of plasma cell differentiation.