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

Etienne Masle-Farquhar; Timothy J Peters; Lisa A Miosge; Ian A Parish; Christoph Weigel; Christopher C Oakes; Joanne H Reed; Christopher C Goodnow

doi:10.1016/j.celrep.2021.110259

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

Cell Rep. 2022 Jan 18;38(3):110259. doi: 10.1016/j.celrep.2021.110259.

Authors

Etienne Masle-Farquhar¹, Timothy J Peters¹, Lisa A Miosge², Ian A Parish³, Christoph Weigel⁴, Christopher C Oakes⁴, Joanne H Reed¹, Christopher C Goodnow⁵

Affiliations

¹ The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia.
² Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
³ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.
⁴ Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
⁵ The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia. Electronic address: c.goodnow@garvan.org.au.

PMID: 35045301
DOI: 10.1016/j.celrep.2021.110259

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: B1 B cell; CD21low B cell; CLL; EGR2; EGR3; age-associated B cell; anergy; atypical-memory B cell; double-negative B cell; tolerance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmune Diseases / immunology
Autoimmune Diseases / metabolism
Autoimmunity / immunology
B-Lymphocyte Subsets / immunology
B-Lymphocyte Subsets / metabolism
B-Lymphocytes / immunology*
B-Lymphocytes / metabolism
Clonal Anergy / immunology*
Early Growth Response Protein 2 / immunology*
Early Growth Response Protein 2 / metabolism
Early Growth Response Protein 3 / immunology*
Early Growth Response Protein 3 / metabolism
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / immunology
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
Male
Mice
Receptors, Complement 3d / immunology

Substances

Early Growth Response Protein 2
Receptors, Complement 3d
Early Growth Response Protein 3