Progression through the stages of lymphocyte development requires coordination of the cell cycle. Such coordination ensures genomic integrity while cells somatically rearrange their antigen receptor genes [in a process called variable-diversity-joining (VDJ) recombination] and, upon successful rearrangement, expands the pools of progenitor lymphocytes. Here we show that in developing B lymphocytes, the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 are critical for maintaining quiescence before precursor B cell receptor (pre-BCR) expression and for reestablishing quiescence after pre-BCR-induced expansion. These RBPs suppress an evolutionarily conserved posttranscriptional regulon consisting of messenger RNAs whose protein products cooperatively promote transition into the S phase of the cell cycle. This mechanism promotes VDJ recombination and effective selection of cells expressing immunoglobulin-μ at the pre-BCR checkpoint.

Post-transcriptional regulation of mRNA by the RNA binding protein HuR (Elavl1) is required in B cells for the germinal centre reaction and for the production of class-switched antibodies in response to T-independent antigens. Transcriptome-wide examination of RNA isoforms, abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interaction, revealed that HuR-dependent mRNA splicing affects hundreds of transcripts including the dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase complex (αKGDH). In the absence of HuR, defective mitochondrial metabolism results in high amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for B cell proliferation and differentiation.

Antibody affinity maturation occurs in germinal centres (GC) where B cells cycle between the light zone (LZ) and the dark zone. In the LZ GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from T helper cells that promotes their rapid proliferation. Here we show that the RNA binding protein PTBP1 is necessary for the progression of GC B cells through late S-phase of the cell cycle and for affinity maturation. PTBP1 is required for the proper expression of the c-MYC-dependent gene program induced in GC B cells receiving T cell help and directly regulates the alternative splicing and abundance of transcripts increased during positive selection to promote proliferation.