Uncontrolled CD21low age-associated and B1 B cell accumulation caused by failure of an EGR2/3 tolerance checkpoint

Masle-Farquhar, E; Peters, TJ; Miosge, LA; Parish, IA; Weigel, C; Oakes, CC; Reed, JH; Goodnow, CC

Author(s): Masle-Farquhar, E; Peters, TJ; Miosge, LA; Parish, IA; Weigel, C; Oakes, CC; Reed, JH; Goodnow, CC;
Details: Publication Year 2022-01-18,Volume 38,Issue #3,Page 110259
Journal Title: Cell Reports
Publication Type: Research article
Abstract: CD21(low) 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. CD21(low) 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 CD21(low) B cell formation, and inform how NFATC1 or EGR2 mutations promote B1 cell-derived chronic lymphocytic leukemias.
Keywords: Animals; Autoimmune Diseases/immunology/metabolism; Autoimmunity/immunology; B-Lymphocyte Subsets/immunology/metabolism; B-Lymphocytes/*immunology/metabolism; Clonal Anergy/*immunology; Early Growth Response Protein 2/*immunology/metabolism; Early Growth Response Protein 3/*immunology/metabolism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell/immunology/metabolism; Male; Mice; Receptors, Complement 3d/immunology; B1 B cell; CD21low B cell; Cll; Egr2; Egr3; age-associated B cell; anergy; atypical-memory B cell; double-negative B cell; tolerance
Department(s): Laboratory Research
PubMed ID: 35045301
Publisher's Version: https://doi.org/10.1016/j.celrep.2021.110259
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2021.110259
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-31 03:38:56

Last Modified: 2025-01-31 03:40:50