BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells
Introduction
Protective immunity against a broad range of pathogens requires the ongoing generation of lymphocytes with diverse antigen receptor specificities. This requirement is achieved via random assortment of germline encoded V(D)J genes in developing lymphocytes. An inherent tradeoff within this process, however, is creation of autoreactive receptors with the potential to elicit an autoimmune response. For B cells, autoreactive specificities are removed or segregated from the developing repertoire at discrete stages in the bone marrow and periphery. Immature B cells with newly rearranged B cell receptors (BCRs) are first tested for reactivity towards self-antigens in the bone marrow. Depending on the strength of BCR signaling and the physical form of the antigen, reactive cells are deleted [1], subjected to receptor editing [2] or rendered functionally anergic [3]. Importantly, despite these processes, up to 40% of transitional B cells (alternatively referred to as recent bone marrow emigrants, or transitional type 1 [T1] or type 2 [T2] cells) continue to exhibit some level of self-reactivity. Splenic transitional B cells are subjected to additional selective processes that further cull self-reactivity before their maturation and entry into the mature, naïve follicular (FM) or marginal zone (MZ) peripheral B cell compartments. Paradoxically, BCR signals also appear to be necessary for the positive selection of splenic transitional B cells. Importantly, a growing body of recent work indicates that BCR signals synergize with B cell intrinsic, non-antigenic signals, including biochemical events triggered by receptors binding to BAFF, CD40L, and Toll-like receptor (TLR) ligands, and that this interplay is crucial in determining the selection program induced in a given B cell. A better understanding for how the interplay of these BCR and non-BCR signals ultimately shapes the repertoire of the mature, naïve compartment is crucial for a complete understanding of both autoimmune susceptibility, as well as early pathogen-triggered antibody responses to acute infection.
Section snippets
BCR as a master regulator of positive selection
In both central and peripheral B cell development, maintaining an ‘intermediate’ level of BCR signaling is necessary for cell survival and maturation. After emigrating from the bone marrow, tonic BCR signaling is required for the persistence of both transitional and mature B cells via provision of canonical NFκB-dependent and/or PI3K-dependent pro-survival signals [4, 5, 6]. Correspondingly, impaired BCR signaling, such as reduced Btk activity in xid mice, results in reduced B cell maturation [7
Crosstalk between the BCR and BAFF-R pathways (Figure 1a)
The importance of cytokine BAFF in B cell survival and homeostasis has been well studied [15] and systemically produced BAFF, generated by fibroblastic reticular cells [16], appears to be particularly important for this process. Although BAFF can bind to three alternative receptors — BAFF-R, TACI, and BCMA — BAFF-R appears to play the dominant role in peripheral B cell maturation. Transitional B cells predominantly express BAFF-R and mice deficient in either BAFF or BAFF-R exhibit an identical
Excess BAFF in autoimmunity (Figure 1b)
Serum, as well as localized, BAFF levels are elevated in many subjects suffering from autoimmune disorders [23]. Transgenic mice overexpressing BAFF (BAFF-Tg) provide useful models to study its impact on disease progression. BAFF-Tg mice display B cell hyperplasia and develop lupus-like disease. Excess BAFF rescues low-affinity self-reactive transitional cells that are normally outcompeted for entry into B cell follicles (presumably through BAFF-R survival signaling), allowing self-reactive B
Crosstalk between the BCR and CD40 pathways (Figure 2a)
Emerging data suggest that CD40 signaling, similar to BAFF-R, may also modulate transitional B cell selection in concert with the BCR program. CD40 engagement promotes both the alternative and classical NFκB prosurvival pathways [27] . In addition to the well-described upregulation of CD40L following T cell activation, CD40L is also constitutively expressed by naïve CD4 T cells [28]. A range of in vitro observations have long implicated CD40 signals in modulating transitional B cell survival
Excess CD40 signals in autoimmunity (Figure 2b)
An autoimmune risk variant in the phosphatase, PTPN22, can be used as a model for understanding how dual enhanced BCR and CD40 signaling may shape transitional B cell function and selection. Subjects with the PTPN22-R620W risk variant exhibit altered B cell selection and increased B cell CD40 expression and activation [31]. In addition, human subjects with the risk allele and the knock-in murine model share many features, including an increase in the size of the transitional B cell compartment
Crosstalk between the BCR and TLR pathways (Figure 3a)
A cardinal feature of the autoimmune disorder, systemic lupus erythematous (SLE), is generation of autoantibodies reactive towards a relatively restricted spectrum of self-antigens, including nucleic acids (dsDNA, RNA) and proteins co-associated with other apoptotic cell materials. Crosstalk between the BCR and TLR signaling pathways play a crucial role in orchestrating loss of peripheral B cell tolerance to such antigens [34, 35]. BCR engagement with self-antigens facilitates their trafficking
Excess TLR signals in autoimmunity (Figure 3b)
Dissecting the role of dual TLR and BCR signals in regulating positive selection of the naïve B cell compartment is best understood in the setting of the primary immunodeficiency, Wiskott–Aldrich syndrome (WAS), whereby complete or partial loss-of-function mutations in the WAS protein (WASp) affects actin polymerization and cytoskeleton organization. WAS subjects exhibit a high prevalence of spontaneous systemic autoimmunity, and consistent with this human data, B cell-intrinsic WASp deficiency
Conclusions
We have summarized how the BCR signal pathway modulates negative and positive selection mechanisms in transitional cells through its integration with additional peripheral factors (Figure 1, Figure 2, Figure 3), as well as evaluated the role that altered signal pathways play in contributing to the loss of B cell tolerance in various autoimmune diseases (Figure 1, Figure 2, Figure 3). Although Figure 1, Figure 2, Figure 3 provide a simplified overview of the crosstalk between dual BCR and
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by NHLB1, NICHD, NIDDK and NIAID of the National Institutes of Health under award numbers: R01HL075453 (DJR), R01A1084457 (DJR), R01A1071163 (DJR), DP3DK097672 (DJR), DP3DK097672-01S1 (GM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support provided by the Benaroya Family Gift Fund; and by a Cancer Research Institute Pre-doctoral Training Grant (NSK).
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