Nur77 Links Chronic Antigen Stimulation to B Cell Tolerance by Restricting the Survival of Self-Reactive B Cells in the Periphery

Abstract

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.

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

“…GFP LO B cells 15. In subsequent work, we further excluded the contribution of other immunoreceptor pathways (especially those medi-Tg, and found that dsDNA-reactive λ1 + B cells from these mice turn on GFP reporter expression very early in development, and express much higher levels in maturity than either WT or V H 3H9/κ B cells, consistent with chronic self-antigen stimulation 27. Conversely, V H 3H9 Tg B cells expressing Vλ3 L chains (aka λx) that are known to censor DNA-reactivity express much lower levels of GFP, as do rare "escapee" B cells that express endogenous H chains.…”

“…22 This last phenomenon is termed follicular exclusion, depends on the chemokine receptors CXCR5 and CCR7, and has been described not only in the IgHEL model, but also in the V H 3H9 and Ars/A1 models. 27 Indeed, the two-signal model of B cell activation was initially proposed by Bretscher and Cohn in part as a strategy to discriminate self from non-self.…”

“…E, Schematic depicts relative surface expression of IgM (blue) and IgD (red) BCRs on B cells with increasing expression of GFP (and therefore increasing self-reactivity) across the mature Fo B cell repertoire 25,26 We generated Nur77-eGFP reporter mice harboring the sd-V H 3H9 Tg, and found that dsDNA-reactive λ1 + B cells from these mice turn on GFP reporter expression very early in development, and express much higher levels in maturity than either WT or V H 3H9/κ B cells, consistent with chronic self-antigen stimulation. 27…”

“…We found that Nur77-deficient B cells exhibit enhanced survival and proliferation relative to WT B cells in response to acute BCR stimulation, but exhibit no competitive advantage in the context of co-stimulation, in the form of either TLR stimuli or signals that mimic T cell help (unpublished data, Zikherman lab). 27 We postulate that negative regulation by Nur77 of both naive and self-reactive B cells (which exist on a continuum!) serves to confer dependence upon a second signal and thus helps maintain tolerance by restricting survival of B cells that receive signal one either acutely or chronically in the absence of signal two.…”

“…iting, central deletion, follicular exclusion and anergy, we discovered that Nur77 restrains the survival of mature self-reactive B cells in vitro and in vivo, particularly in settings where the B cell survival factor BAFF is limiting, and this can be rescued entirely by supplemental BAFF 27. Nur77-deficiency also 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 Tg mice.…”