MiR-148a Regulates B Cell Response And Central Tolerance

MicroRNAs play important roles in many aspects during biological process,including B cell development,activation,proliferation and differentiation.Although miR-148a is highly expressed in B cell derived plasma cells,its role in humoral response is largely unknown.To understand the role of miR-148a in B cell development and function,we generated miR-148a/148b/152 deficient(TKO)mice and miR-148a transgenic(Tg)mice.B cell development is comparable in both TKO and Tg bone marrow chimera mice.However,GC B cell differentiation is significantly impaired when miR-148a overexpressed,antibody response is diminished after immunization.In vitro B cell culture system showed GC B cell differentiation and class switch recombination are significantly reduced in miR-148a overexpressed B cells.B cell proximal signaling is severely impaired after BCR crosslinking.CLIP(CrossLinking and ImmunoPrecipitation)showed that miR-148a could target Blimp 1 and Bip directly,early Blimp 1 upregulation and Bip downregulation coordinately inhibit GC B cell differentiation and antibody response.Taken together,our findings demonstrate that miR-148a plays a critical and intrinsic role in B cell activation,GC B formation and class switch recombination.The regulation network of microRNA is hotly debated physiologically,as whether a miRNA exerts its biological function through regulating a small number of key targets or through small changes in the expression of hundreds of target genes.We previously identified miR-148a as a critical regulator of B cell central tolerance in IgMb mouse model,but exactly how many target genes involved,beyond Bim,Pten and Gadd45a,is not clear.Here,we performed a systematic functional analysis of the other miR-148a target genes in B cell central tolerance models in vitro and in vivo.Our results show that those additional target genes play a minimal role,if any,in miR-148a mediated control of B cell central tolerance.Here,we evaluate in physiological conditions,there is indeed,that the function of miRNA is mediated by a few key target genes.