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 are autoantibody enriched and poised for plasma cell differentiation. These cells overaccumulate in chronic infections, autoimmune disease, and immunodeficiency, posing the question of what checkpoints normally oppose their accumulation. Here, we reveal a critical role for 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- to 20-fold greater than normal and overexpress 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 downregulation by self-antigens, and EGR2/3 deficiency abolishes this cardinal feature of B cell anergy. These results explain the 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. [Display omitted] •Follicular B cells express Egr2 proportionally to IgM cell-surface downregulation•Egr2/3 deficiency decreases Zfp318 and increases surface IgM expression•EGR2 and EGR3 are transcriptional regulators of atypical CD21low B cells•EGR2 and EGR3 prevent excessive accumulation of CD21low B cells and B1 cells Chronic B cell receptor signaling induces the transcription factors EGR2/3. EGR2 mutations recur in chronic lymphocytic leukemia. Masle-Farquhar et al. show that EGR2/3 regulate the cardinal features of B cell anergy and prevent the overaccumulation of mouse B1 lymphocytes and atypical CD21low B lymphocytes resembling those that accumulate with age, chronic infections, immunodeficiency, and autoimmunity