To defend an organism against invaders such as viruses and bacteria, cells of the immune system need to recognize and respond to foreign microbes. However, these immune cells must also avoid attacking ‘self’ – for example, the healthy tissues of the body – as this could lead to autoimmune disease.

B cells are a type of immune cell that is essential in order to produce antibodies, protective proteins that can identify and defend against a broad range of germs: in addition, certain antibodies can also recognize ‘self’. When a B cell first develops, it places its antibody on its surface and uses this protein as a receptor (termed ‘B cell receptor’) to sense its surroundings.

Prior to mounting an immune response, B cells carry two closely related versions of the B cell receptor on their surface: IgM and IgD. Both IgM and IgD perform many of the same roles and can largely substitute for one another. However, B cells that recognize ‘self’ decrease their levels of IgM but keep high amounts of IgD on their surface. It is unclear why this is the case, but one possibility is that IgM and IgD may see ‘self’ differently.

To investigate this, Noviski et al. used mice with B cells that only carry either IgM or IgD, and tracked how these cells reacted to molecules from ‘self’ and foreign origins. IgM-only B cells reacted more strongly to ‘self’ molecules than IgD-only cells, which suggests that IgM is more sensitive to ‘self’ than IgD. In fact, in mice which are at risk for an autoimmune disease similar to lupus, deleting the IgM receptor prevented antibodies against ‘self’ from being produced. Therefore, reducing the amount of IgM receptors may be a way to keep B cells that are reactive against ‘self’ from inappropriately attacking the host. Meanwhile, the IgD receptor still allows B cells to mount protective antibody responses against foreign microbes.

Future studies are necessary to determine whether these differences between IgM and IgD also exist in humans. If this is the case, blocking the IgM receptor could become a new kind of treatment for certain autoimmune diseases.

The pre-immune mature naïve B cell compartment must balance the need for a diverse antibody repertoire with the risk of autoantibody-mediated disease. Early in development, B cells randomly rearrange their immunoglobulin genes through VDJ recombination and encounter a series of tolerance checkpoints that serve to remove autoreactive B cell receptors (BCRs) from the repertoire. Strongly autoreactive immature B cells rearrange additional light chains to ‘edit’ their autoreactivity, and they ultimately undergo deletion if this is unsuccessful (Shlomchik, 2008). Yet, despite stringent counter-selection of autoreactivity, the mature follicular (Fo) B cell compartment retains cells reactive towards endogenous antigens (Wardemann et al., 2003; Zikherman et al., 2012). How these cells are restrained from mounting autoimmune responses is not fully understood.

We previously described a BAC Tg reporter mouse (Nur77-eGFP) in which GFP expression is under the control of the regulatory region of Nr4a1, an immediate early gene rapidly induced by antigen receptor signaling (Mittelstadt and DeFranco, 1993; Winoto and Littman, 2002). We showed that Nur77-eGFP expression in naïve B cells is proportional to strength of antigenic stimulation and consequently to autoreactivity (Zikherman et al., 2012). The most prominent characteristic of GFP^hi reporter B cells is decreased surface IgM BCR relative to GFP^lo cells. Goodnow and colleagues first suggested that IgM downregulation may mark autoreactive B cells in the normal mature repertoire shortly after they reported selective downregulation of IgM in the IgHEL (hen egg lysozyme) BCR Tg/soluble HEL Tg model system of B cell autoreactivity (Goodnow et al., 1988; Goodnow et al., 1989). Indeed, multiple studies in mice and humans have identified naturally occurring IgD⁺IgM^lo cells as autoreactive and ‘anergic’ or functionally unresponsive (Duty et al., 2009; Kirchenbaum et al., 2014; Quách et al., 2011; Zikherman et al., 2012). These results corroborate observations with several BCR transgenic model systems (Cambier et al., 2007). However, whether or how IgM downregulation might constrain autoreactivity remains unclear because naturally-occurring autoreactive B cells maintain high expression of the IgD BCR isotype (Zikherman et al., 2012).

IgM and IgD are splice isoforms of a common precursor heavy chain mRNA (Moore et al., 1981). While they differ in their Fc domains, both BCR isotypes contain the same antigen-binding domain, as well as identical 3-amino acid cytoplasmic tails, and they pair with Igα/β in order to initiate the canonical BCR signaling cascade (Blum et al., 1993; Radaev et al., 2010). However, the expression pattern of the isotypes differs; IgM expression begins as soon as heavy and light chains recombine early in B cell development, and persists until class switch recombination occurs following B cell activation (Chen and Cerutti, 2010). IgD is uniquely co-expressed with IgM during a narrow developmental window on late transitional and mature naïve Fo B cells as a result of alternate splicing regulated by the zinc-finger protein ZFP318 (Enders et al., 2014; Pioli et al., 2014). This suggests that IgD may play a critical role specifically in mature naïve B cells. Initial characterization of IgM- and IgD-deficient mice revealed only mild phenotypes and substantial redundancy; each isotype could mediate B cell development, initiate antibody responses to T-dependent and -independent immunization, and induce normal levels of steady-state serum IgG (Lutz et al., 1998; Nitschke et al., 1993; Roes and Rajewsky, 1993). This is consistent with prior studies in BCR transgenic model systems demonstrating that each isotype alone can mediate B cell development, deletion, and activation (Brink et al., 1992).

IgM and IgD differ structurally; IgD has a much longer, flexible hinge region linking its Fab and Fc regions than IgM does (Chen and Cerutti, 2010). Recently, Ubelhart, Jumaa, and colleagues demonstrated that a short and inflexible hinge confers upon IgM the unique capacity to signal in response to monovalent antigens, while both isotypes can respond to multivalent antigens (Übelhart et al., 2015). However, the Goodnow lab subsequently showed that IgHEL Tg splenic B cells expressing either the IgD or IgM BCR exclusively could mobilize calcium in response to soluble HEL antigen in vitro, and each isotype can mediate a common gene expression program characteristic of anergy in vivo (Sabouri et al., 2016). Therefore, it remains unclear whether IgM and IgD BCRs expressed in an unrestricted B cell repertoire differentially sense bona fide endogenous antigens in vivo, particularly as the identity and nature of such antigens is largely unknown and not restricted to soluble monovalent antigens. For example, 5–10% of circulating naïve B cells in healthy humans express the well-characterized unmutated and autoreactive human heavy chain V-segment IGHV4-34, and these cells exhibit anergy, selective IgM downregulation, and recognize cell-surface antigens on erythrocytes and B cells in vivo (Quách et al., 2011; Reed et al., 2016).

We and others previously hypothesized that downregulation of IgM on Fo B cells might serve to restrain their response to endogenous antigen. Conversely, high expression of IgD on these cells might play a ‘tolerogenic’ role (Zikherman et al., 2012). To determine how IgM and IgD differentially regulate B cell responses to endogenous antigens, we generated Nur77-eGFP reporter mice deficient for either IgM or IgD (Lutz et al., 1998; Nitschke et al., 1993). Using this reporter of antigen-dependent signaling, we show that IgD is less sensitive than IgM to bona fide endogenous antigens in vivo despite higher surface expression and robust responsiveness to receptor ligation in vitro. Indeed, marginal zone (MZ) and B1a cells that express IgD but lack IgM induce less Nur77-eGFP than WT, and this is not attributable to repertoire differences. To further support these observations, we examine a series of cell fate decisions for which in vivo BCR signaling requirements have been previously defined. We show that IgD drives a pattern of development consistent with reduced endogenous antigen recognition, favoring MZ B cell fate and disfavoring B1a cell fate. Similarly, IgD alone is less efficient than IgM at driving SLPC expansion in response to endogenous antigens, a process that requires robust BCR signaling. However, IgD is sufficient for germinal center (GC) B cell differentiation. Our data suggest that reduced endogenous antigen sensing (i.e. signal transduction in response to antigen binding) by the IgD BCR isotype shunts autoreactive IgD^hi IgM^lo Fo B cells away from differentiation into SLPCs. We propose that predominant IgD expression maintains the quiescence of autoreactive B cells in response to chronic endogenous antigen stimulation, and limits autoantibody secretion in the context of rapid immune responses.

We and others previously hypothesized that a major tolerance strategy employed by autoreactive Fo B cells is selective downregulation of IgM. However, since all Fo B cells express a high and invariant amount of surface IgD, it was unclear whether and how loss of IgM expression could affect B cell responses to antigenic stimulation. It was recently reported that IgM, but not IgD, is uniquely responsive to monomeric antigens due to a short and inflexible linker region coupling the Fab and Fc portions of IgM (Übelhart et al., 2015). This could account for selective quiescence of mildly autoreactive B cells to monovalent endogenous antigens. However, the identity and structural characteristics of endogenous antigens are not well understood, and include cell-surface antigens on the surface of red cells and B cells (Quách et al., 2011; Reed et al., 2016). Moreover, recent work from Goodnow and colleagues showed that HEL-specific IgD BCR, when expressed on primary mouse splenocytes, can indeed mobilize calcium in vitro and can mediate gene expression changes in vivo in response to monovalent cognate antigen (Sabouri et al., 2016).

How do our observations help move beyond and reconcile the seemingly contradictory published work on antigen sensing by IgM and IgD? In vitro signaling studies of HEL-specific BCRs by the Jumaa and Goodnow labs differ in several important ways; the former work assesses calcium signaling in pre-B cells that lack Slp-65 expression, while the latter studies splenic B cells with a considerably more mature phenotype. In addition, differences in reagents or strength of stimulus may also contribute to opposing conclusions. Our data suggests that the reduced sensitivity of IgD to bona fide endogenous antigen may lie somewhere between these two extremes; we find that IgD can sense endogenous antigens, just less efficiently than IgM. Consistent with this conclusion, both HEL-specific IgM and IgD BCRs can mediate B cell anergy and drive a common gene expression program in response to chronic high affinity soluble antigen exposure in vivo (Brink et al., 1992; Sabouri et al., 2016).

Here we show that B cells expressing IgD BCR alone inefficiently sense endogenous antigens, and exhibit impaired in vivo cell fate decisions that are dependent upon BCR signal strength. This is epitomized by dramatic skewing of IgD-only B cells away from the B1a and towards the MZ fate in a competitive setting. Importantly, signal transduction mediated by the IgD BCR in response to anti-Igκ stimulation in vitro is intact for all assayed parameters, suggesting that antigen sensing and signal initiation rather than signal transduction downstream of IgD is impaired. We propose that this impaired sensing is conferred by structural properties of IgD, either through direct binding of antigen and signal transduction through the BCR or through differential pairing with co-receptors that directly modulate the BCR signaling pathway.

Characterization of bona fide endogenous antigens that drive Nur77-eGFP expression in the polyclonal repertoire is necessary in order to further dissect the biophysical basis for reduced antigen sensing by IgD in vivo. These antigens may not be exclusively restricted to those that are germline-encoded or generated by host enzymes; rather they may include non-inflammatory antigens taken up through the gastrointestinal tract and recognized by specific BCRs. At least some relevant endogenous antigens may be membrane-bound (Quách et al., 2011; Reed et al., 2016), and recent studies have illustrated the importance of membrane spreading, contraction, and stiffness discrimination in BCR signaling (Fleire et al., 2006; Shaheen et al., 2017). We propose that relevant endogenous antigens are presented in contexts that do not efficiently trigger signaling through the flexible structure of IgD. This might explain the discrepancy between weak responsiveness of IgD to endogenous antigens in vivo and strong signaling in response to crosslinking antibodies in vitro.

An alternative mechanism is that differential clustering of co-receptors with IgD and IgM might influence how BCR signals are integrated in vivo. It has long been proposed that there are not only quantitative, but also qualitative differences between IgM and IgD signaling. Early studies of IgM and IgD signaling in cell lines suggested that kinetics but not quality of signaling triggered by each isotype differed (Kim and Reth, 1995). However, we have been unable to identify a difference in kinetics of BCR signaling in primary IgM- or IgD-deficient B cells in vitro. More recently, studies using TIRF, dSTORM, and PLA (proximity ligation assay) showed that IgD is more densely clustered on the cell surface than IgM, and these distinct IgM- and IgD-containing ‘islands’ are differentially associated with co-receptors such as CD19 in resting and activated B cells (Kläsener et al., 2014; Maity et al., 2015; Mattila et al., 2013). Since function of the ITIM-containing inhibitory co-receptor CD22 depends on its ability to efficiently access the BCR, differences in cluster density of IgM and IgD might render them differentially sensitive to such inhibitory tone (Gasparrini et al., 2016). It is possible that differential association with such co-receptors contributes to differences in the function of the IgM and IgD BCRs in vivo by modulating BCR signal strength, or by selectively perturbing specific downstream signaling events.

In addition to B cell co-receptors that have long been known to directly modulate canonical BCR signaling, a growing list of immunoreceptors expressed on B cells have more recently been shown to require expression of the BCR for optimal function; Becker et al. have shown that expression of the IgD BCR is critical for CXCR4-dependent signaling (Becker et al., 2017). This may influence the biology of B cells expressing only IgM; indeed, CXCR4-deficient B cells exhibit reduced plasma cell migration from spleen to bone marrow (but intact splenic SLPC responses) (Nie et al., 2004). Importantly, defective CXCR4 signaling in IgM-only B cells could not account for reduced Nur77-eGFP expression in IgD-only B cells because reporter expression is insensitive to CXCR4 signaling (Figure 1—figure supplement 1C). Nor would it account for skewed cell fate decisions by IgD-only B cells in competition with wild type B cells, both of which retain intact CXCR4 signaling. B cell responses to TLR4 ligands also require expression of the BCR, but importantly, canonical TLR ligands do not exhibit selective dependence on either the IgM or the IgD isotypes (Figure 1—figure supplement 3A). Finally, recent work establishes a role for the Fc-receptor for IgM in modulating B cell responses, and could therefore play a role downstream of serum IgM that is absent in IgM^−/− mice (Nguyen et al., 2017a; Nguyen et al., 2017b). We control for this effect by confirming that all phenotypes in this study are cell-intrinsic and independent of secreted IgM.

Accumulating evidence suggests that strong BCR signals favor SLPC over GC fate (Chan et al., 2009; Nutt et al., 2015; Paus et al., 2006). This is thought to be transcriptionally mediated at least in part by loss of Ets1 expression and induction of Irf4 in a BCR signal-strength dependent manner (Nutt et al., 2015). Here we show that IgM and IgD are each sufficient to drive GC responses, but IgD is less efficient at promoting SLPC fate in response to endogenous antigens, implying that IgD^hi IgM^lo B cells may similarly be shunted away from SLPC responses. This discrepancy is unlikely to be attributable to differences in antigen capture and presentation by the IgM and IgD BCRs, as GC entry is highly T cell-help dependent. Instead, we provide evidence to suggest that reduced antigen-dependent BCR signals are transduced in vivo by IgD. We show that, in the absence of Lyn, Ets1 downregulation and unswitched PC expansion require the IgM BCR. IgM^−/−Lyn^−/− mice phenocopy Btk^loLyn^−/− mice; both strains are protected from Ets1-downregulation, PC expansion, and anti-dsDNA autoantibody production in vivo (Mayeux et al., 2015; Whyburn et al., 2003). This suggests that robust Btk-dependent Ets-1 downregulation in response to endogenous antigens relies upon efficient antigen sensing by the IgM BCR and is important to drive unswitched PC expansion in the absence of Lyn. It will be important to explore whether a similar mechanism accounts for impaired IgG1⁺ SLPC responses by Lyn-sufficient B cells with low or absent IgM expression.

We propose that the purpose (and consequence) of IgM downregulation on autoreactive B cells is to limit their direct differentiation into SLPCs in response to chronic endogenous antigen stimulation, and prevent secretion of auto-antibodies in the context of an acute humoral immune response (Figure 7—figure supplement 2A). However, IgD is sufficient to drive germinal center differentiation without the contribution of IgM. This has been well-demonstrated both in the present study as well as prior work (Lutz et al., 1998). Indeed, not only are autoreactive IgD^hi IgM^lo B cells competent to enter the germinal center, they appear to do so with greater efficiency, perhaps due in part to improved survival (Sabouri et al., 2016; Sabouri et al., 2014). It is worth emphasizing that selection pressures and tolerance mechanisms operating within the germinal center must independently ensure that somatic hypermutation both abolishes germ-line-encoded autoreactivity and prevents de novo acquisition of autoreactivity. Goodnow and colleagues recently showed that autoreactive BCRs can indeed be ‘redeemed’ by somatic hypermutation, providing proof-of-principle that entry of autoreactive B cells into the GC does not necessarily pose a risk to the organism (Sabouri et al., 2014).

Why, though, are autoreactive B cells preserved in the periphery and not deleted? Why is IgD necessary at all? One suggestion is that such BCRs are retained in the pre-immune B cell compartment to fill holes in the repertoire, and that IgD is essential for their survival; indeed, it has been shown that loss of IgD expression, with or without compensatory upregulation of IgM, leads to loss of mature naïve B cells in competition (Roes and Rajewsky, 1993; Sabouri et al., 2016). We similarly find that IgD-only B cells have a profound competitive advantage in the follicular B cell compartment relative to IgM-only (but not WT) B cells, implying an obligate survival function for the IgD isotype BCR. This is consistent with a well-appreciated pro-survival function of the BCR as demonstrated by Rajewsky and colleagues (Kraus et al., 2004; Lam et al., 1997). Since IgD expression is needed to keep IgM^lo B cells alive, this may explain why IgD expression facilitates a broad dynamic range of IgM expression across the B cell repertoire (Figure 1B,C), allowing B cells to fine-tune the intensity of their SLPC responses according to their autoreactivity. IgD expression on IgM^lo cells could serve to mediate antigen capture and participation in T-dependent immune responses, while simultaneously limiting SLPC responses as we show here.

We demonstrate here for the first time that IgD BCRs sense endogenous antigen more weakly than IgM BCRs in vivo, are inefficient at driving SLPC responses to endogenous antigens, and thereby may function to divert autoreactive follicular B cells from direct PC differentiation. We propose that this property of the IgD BCR limits generation of auto-reactive antibodies in the context of immediate humoral immune responses. Taken together with recent work from the Jumaa and Goodnow groups, we propose a unified model of how IgM downregulation in the face of high IgD expression regulates the fate of naïve autoreactive B cells in vivo while retaining their contribution to the mature BCR repertoire.

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Author details

1. Mark Noviski

   Biomedical Sciences (BMS) Graduate Program, University of California San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8072-1059

2. James L Mueller

   Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

3. Anne Satterthwaite

   Department of Immunology, UT Southwestern Medical Center, Dallas, United States

   Contribution

   Resources, Writing—review and editing

   Competing interests

   No competing interests declared

4. Lee Ann Garrett-Sinha

   Department of Biochemistry, University at Buffalo, The State University of New York, Buffalo, United States

   Contribution

   Resources, Writing—review and editing

   Competing interests

   No competing interests declared

5. Frank Brombacher

   1. International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
   2. Institute of Infectious Diseases and Molecular Medicine, Division of Immunology, Faculty of Health Sciences, University of Cape Town & Medical Research Council (SAMRC), Cape Town, South Africa

   Contribution

   Resources, Writing—review and editing

   Competing interests

   No competing interests declared

6. Julie Zikherman

   Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   julie.zikherman@ucsf.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0873-192X

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