ERP132489 PRJEB48165 ena-STUDY-GARVAN INSTITUTE OF MEDICAL RESEARCH-18-10-2021-07:40:53:795-228 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, enriched for autoantibodies and poised for plasma cell differentiation, accumulate in large numbers 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. In the absence of EGR2 and EGR3 within B cells, CD21low and B1 B cells 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. Transcriptional profiling of Egr2/3-deficient murine CD21-low atypical B cells and B1 cells. CD21low age-associated or atypical memory B cells, enriched for autoantibodies and poised for plasma cell differentiation, accumulate in large numbers 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. In the absence of EGR2 and EGR3 within B cells, CD21low and B1 B cells 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. ENA-FIRST-PUBLIC 2021-12-17 ENA-LAST-UPDATE 2021-12-17