期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 10, 页码 2907-2923出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801565
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资金
- National Institute of Allergy and Infectious Diseases [5T32AI007334-28]
- Howard Hughes Medical Institute Medical Research Fellows Program
- National Science Foundation [1650113]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR069520, K08AR059723]
- Rheumatology Research Foundation
- Direct For Education and Human Resources [1650113] Funding Source: National Science Foundation
- Division Of Graduate Education [1650113] Funding Source: National Science Foundation
Nur77 (Nr4a1) belongs to a small family of orphan nuclear receptors that are rapidly induced by BCR stimulation, yet little is known about its function in B cells. We have previously characterized a reporter of Nr4a1 transcription, Nur77-eGFP, in which GFP expression faithfully detects Ag encounter by B cells in vitro and in vivo. In this study, we report that Nur77 expression correlates with the degree of self-reactivity, counterselection, and anergy among individual B cell clones from two distinct BCR transgenic mouse models but is dispensable for all of these tolerance mechanisms. However, we identify a role for Nur77 in restraining survival of self-reactive B cells in the periphery under conditions of competition for a limited supply of the survival factor BAFF. We find that Nur77 deficiency results in the progressive accumulation of self-reactive B cells in the mature repertoire with age and is sufficient to break B cell tolerance in V (H)3H9 H chain transgenic mice. We thus propose that Nur77 is upregulated in self-reactive B cells in response to chronic Ag stimulation and selectively restricts the survival of these cells, gradually pruning self-reactivity from the mature repertoire to impose a novel layer of peripheral B cell tolerance.
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