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

Abstract

Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self-reactive B cell receptors (BCRs) from populating the periphery.Despite this, modest self-reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77-eGFP, expression of which scales with the degree of self-reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self-reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance. K E Y W O R D Sanergy, B cell, IgD, IgM, Nur77/Nr4a1, tolerance Previous work from our laboratory exploiting an in vivo reporter of antigen recognition, Nur77-eGFP BAC Tg, addresses this important point ( Figure 1A). 15 GFP expression in this reporter line is under the control of the regulatory region of Nr4a1/ Nur77. Nr4a1-3 encode a small family of orphan nuclear hormone receptors which were originally cloned as signal-dependent primary response genes (also known as immediate-early genes), and are highly upregulated by a range of mitogens, including antigen receptor stimulation. [16][17][18] Consequently, antigen stimulation rapidly triggers reporter expression in B and T cells in vitro ( Figure 1B), and GFP is also induced by infection or immunization in antigen-specific lymphocytes in

Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

“…Even in non-autoimmune prone genetic backgrounds, some aspects of deletion, developmental arrest and anergy may be overcome by augmenting anti-apoptotic pathways (23) or by provision of T cell help (24) and innate stimuli (25). While these have been informative, the typical readouts for these experiments are technically limited and include the tracking of BCR-transgenic cells and/or indirect probing for the frequency of self-reactive BCRs by cloning and screening them as recombinant antibodies by ELISA (26). Whether these readouts directly reflect ongoing autoreactivity by a physiological repertoire remains unclear.…”

“…Chronic sensing of self-antigen in the periphery enforces an anergy transcriptional program (10,27) and the downregulation of surface IgM (26). The two key goals of this are 1) dampening signal transduction via the BCR upon self-ligation and 2) reducing the probability of encountering T cell help.…”

“A negative feedback loop mediated by the NR4A family of nuclear hormone receptors restrains expansion of B cells that receive signal one in the absence of signal two”

“…We previously characterized a fluorescent reporter of Nr4a1 expression (NUR77-EGFP BAC Tg) that scales with the extent of Ag stimulation in vitro and in vivo, and therefore serves to mark naturally occurring autoreactive T and B cells in healthy mice [22][23][24][25][26] . We showed that this reporter correlates with self-reactivity in three different BCR Tg models 25,[27][28][29] . More recently, we have identified a role for NUR77/Nr4a1 in imposing a novel layer of B cell tolerance in vivo by mediating competitive elimination of chronically Ag-stimulated self-reactive B cells in settings with a limiting supply of the B cell survival factor BAFF 28 .…”

“…cells acutely activated only by Ag are normally restrained, and helps to enforce their dependence upon co-stimulation. Indeed, we have previously identified upregulation of NUR77-EGFP expression in self-reactive B cells in response to chronic BCR engagement, and isolated a specific role for NUR77 in restricting the survival of such cells, particular in settings where the B cell survival factor BAFF is limiting25,[27][28][29] . It has been proposed that certain features of anergic B cells, including reduced half-life, may be understood in part as a "special case" of the acute B cell response to signal 1 in the absence of signal 266 .…”

The periphery is the dominant site of B-cell deletion in a polyclonal repertoire

“…Fas) also limit the effector function of autoreactive B cells. Mutations in those additional tolerance checkpoints would permit less stringent control of these anergic B cells [22,29]. Evidence of this can be drawn from neutralising antibodies against HIV which are isolated from hosts with 'relaxed' B cell tolerance and often originate from germline autoreactive precursors [30].…”