NFkB cRel protein amount determines the selection of germinal center B cells 4004

Abstract Description Germinal centers (GCs) are the site of B cell proliferation coupled with somatic hypermutation of the B cell receptors to produce high-affinity antibodies. GC B cells circulate between two distinct zones: the light zone (LZ) and the dark zone (DZ). It has been demonstrated that the transcription factor NFkB cRel is required for B cell proliferation and GC B cell maintenance. cRel-deleted GC B cells show reduced somatic hypermutation and affinity maturation. On the contrary, transgenic overexpression of cRel in GC B cells does not affect somatic hypermutation and reduce, if any, affinity maturation. Therefore, the function of cRel in regulating GC B cell selection remains unknown. To understand the function of cRel in GC B cell selection, we have generated cRel fluorescence reporter mice and measured the kinetics of cRel expression at the protein level in GC B cells. We found that about 10% of LZ B cells increased cRel expression compared to DZ B cells. Surprisingly, cRel expression at the mRNA level remains similar in low and high cRel protein-expressing GC B cells. We found that high cRel-expressing LZ B cells have a higher somatic hypermutation and increased expression of genes, such as Myc and CyclinD2, required for GC B cell selection. Overall, our results suggest that cRel protein but not transcript levels regulate GC B cell selection. Our studies resolve conflicting findings about the function of cRel in GC B cell affinity maturation. Funding Sources NIH/NIAID-1R56AI177789 American Society of Hematology Scholar Award Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)