Molecular Mechanistic Insight Into BCL6 And BACH2-mediated Germinal Center Response

The transcription repressor BCL6 serves as a master regulator during the germinal center(GC)reactions for the production of high-affinity antibodies.Aberrant GC reactions have been implicated in the genesis of autoimmune diseases and B cell lymphomas.BCL6 is essential for the development and function of GC B cells,and this is related to its ability in direct suppression of a series of genes controlling B cell activities.Here we show that BCL6 is a negative regulator of ligands(CD274/PD-L1,CD273/PD-L2)of the co-inhibitory receptor CD279(PD-1)in GC B cells.Induced deletion of Bcl6 resulted in upregulated expression of PD-L1/2 as well as reduced GC B cell numbers in vivo.In addition,the expression levels of PD-1 ligands and BCL6 were inversely correlated either in GC B cell development or in human GC-derived lymphoma specimens.Mechanically,BCL6 inhibits the expression of PD-L1/2,either directly by binding to the promoter region of PD-L1 and intron 2 of PD-L2,or indirectly by inhibiting the STAT1/3-IRF1-IFNg pathway.These suppressive functions exerted by BCL6 are accomplished via its BTB domain.In the end,PD-1 blockade facilitated cell survival by maintain the follicular T cell pool in the presence of Bcl6-null GC B cells.In conclusion,the expression of BCL6 can dampen the PD-L1/L2-PD-1 signaling to sustain the follicular T cells size during GC development.The transcription repressor BACH2 serves as a master regulator during germinal center(GC)reactions,but the mechanisms are still unclear.In this study,we show that the AIDCre mediated ablation of Bach2 in GC has significant influences on germinal center formation and class-switch recombination(CSR)responses.Both the number and size of the GCs decreased in Bach2f/f AIDCre mice with an almost lost of light zone(LZ)and reduced T follicular helper cells(TFH),which are specialized in providing cognate help to B-cells for the formation of GCs.Bach2-null GC B cells also displayed aberrant CSR,although no alteration was detected in activation-induced cytidine deaminase(AID)expression.Additionally,Bach2-null GC B cells underwent increased apoptosis but normal proliferation.In conclusion,considering that the germinal center is a highly active structure in which proliferation and apoptosis occur constantly,so we conjecture BACH2 may regulate GC formation and CSR by DNA damage suppression.