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Uncontrolled CD21 low age-associated and B1 B cell accumulation caused by failure of an EGR2/3 tolerance checkpoint.

Uncontrolled CD21 low age-associated and B1 B cell accumulation caused by failure of an EGR2/3 tolerance checkpoint.

Authors :
Masle-Farquhar E
Peters TJ
Miosge LA
Parish IA
Weigel C
Oakes CC
Reed JH
Goodnow CC
Source :
Cell reports [Cell Rep] 2022 Jan 18; Vol. 38 (3), pp. 110259.
Publication Year :
2022

Abstract

CD21 <superscript>low</superscript> 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 <superscript>low</superscript> 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 <superscript>low</superscript> B cell formation, and inform how NFATC1 or EGR2 mutations promote B1 cell-derived chronic lymphocytic leukemias.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2021. Published by Elsevier Inc.)

Details

Language :
English
ISSN :
2211-1247
Volume :
38
Issue :
3
Database :
MEDLINE
Journal :
Cell reports
Publication Type :
Academic Journal
Accession number :
35045301
Full Text :
https://doi.org/10.1016/j.celrep.2021.110259