EGR2 ChIP sequencing for study of EGR2/3 loss-of-function in B cells. Uncontrolled CD21low age-associated and B1 B cell accumulation caused by failure of an EGR2/3 tolerance checkpoint

CD21low age-associated or atypical-memory B cells, autoantibody-enriched and poised for plasma cell differentiation, over-accumulate in chronic infections, autoimmune disease and immunodeficiency, posing the question of what checkpoints normally oppose their excessive accumulation. Here, we reveal a critical role for two paralogous calcium-NFAT-regulated transcription factors EGR2 and EGR3 that are induced in self-reactive B cells. CD21low and B1 B cells lacking EGR2 and EGR3 accumulate and circulate in young mice in numbers 10-20 times greater than normal and over-express a large set of EGR2 ChIP-seq target genes including known drivers of plasma cell differentiation. Most follicular B cells constitutively express Egr2 proportionally to surface IgM down-regulation by self-antigens, and EGR2/3 deficiency abolishes this cardinal feature of B cell anergy. These results explain cardinal features of B cell anergy, define a key transcriptional checkpoint repressing CD21low B cell formation, and inform how NFATC1 or EGR2 mutations promote B1 cell-derived chronic lymphocytic leukemias.