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. Author manuscript; available in PMC: 2015 Jul 23.
Published in final edited form as: J Immunol. 2014 Nov 15;193(10):4761–4768. doi: 10.4049/jimmunol.1401805

Role and regulation of CD1d in normal and pathological B cells

Mohammed S Chaudhry *, Anastasios Karadimitris *
PMCID: PMC4512253  EMSID: EMS60317  PMID: 25381357

Abstract

CD1d is a non-polymorphic, MHC class I-like molecule, which presents phosphoand glycosphingo-lipid antigens to a subset of CD1d-restricted T cells called invariant NKT (iNKT) cells. This CD1d-iNKT cell axis regulates nearly all aspects of both the innate and adaptive immune response. Expression of CD1d on B cells is suggestive of the ability of these cells to present antigen to and form cognate interactions with iNKT cells. Herein we summarise key evidence regarding the role and regulation of CD1d in normal B cells and in humoral immunity. We then extend the discussion to B cell disorders, with emphasis on autoimmune disease, viral infection and neoplastic transformation of B lineage cells, where CD1d expression can be altered as a mechanism of immune evasion, and can have both diagnostic and prognostic importance. Finally we highlight current and future therapeutic strategies that aim to target the CD1d-iNKT axis in B cells.

Introduction

CD1d is a non-polymorphic, MHC class I-like, β2-microglobulin-associated molecule, which presents phospho- and glycosphingo-lipid antigens to a subset of immunoregulatory T cells called type I (or invariant) and type II NKT cells (1). While in rodents CD1d is the only lipid-presenting molecule, in humans there are in addition four other CD1 molecules (CD1a, b, c, and e), which interact with lipid-specific T cell subsets distinct to NKT cells.

A hallmark of invariant NKT (iNKT) cells is their use of a semi-invariant αβ T cell receptor. In humans, it comprises an invariant TCRVα24–Jα18 chain paired nearly always with a non-invariant TCRVβ11 chain while in mice the homologous invariant TCRVα14–Jα18 chain pairs with a limited set of TCRVβ chains (TCRVβ2, 7 and 8). iNKT are the best studied subset of CD1d-restricted T cells, and can be described as a type of innate-like lymphocyte which can bridge the innate and adaptive arms of the immune system (2). Following activation, iNKT cells assume a T helper 1 (TH1), TH2 or TH17 functional immune profile and can also exhibit direct cytotoxicity. This diverse range of functions underpins the ability of the CD1d-iNKT axis to play a key role in anti-microbial, anti-tumour and autoimmune responses (3). iNKT cells are activated in response to a range of endogenous and exogenous lipids, with the glycosphingolipid α-galactosylceramide (α-GalCer) being the prototypical and one of the most powerful, although not physiological (i.e. not synthesised in mammalian tissues), stimulating agonists (4).

Transcriptional regulation of CD1d

CD1d is expressed on cells of both myeloid (monocytes, macrophages, dendritic cells) and lymphoid lineage (B lymphocytes, thymocytes but not mature T cells) (5, 6); it is also expressed outside the hematopoietic system, for example on epithelial and vascular smooth muscle cells (7). Expression of CD1d on B cells, the focus of this review, points to the potential of these cells to present lipid antigen to and engage in cross-talk with iNKT cells.

Expression of CD1d is regulated by multiple transcription factors (TF). In humans, the ubiquitous TF SP1 activates transcription by binding to the proximal promoter (8, 9), while LEF-1 represses CD1d transcription by binding to the distal promoter (10). In mice, a minimal proximal promoter region has been identified, which is regulated by various members of the ETS family of TF, including Elf-1 in murine B cells and PU.1 in cells of myeloid lineage (11). Both human and murine CD1d genes share a retinoic acid response element (RARE) in the distal promoter (≈1.5 kb from ATG) (12), and retinoic acid has been shown to increase CD1d expression in myeloid and B cells in vitro (13-15). It is of interest that single nucleotide polymorphisms in the proximal promoter of PWD inbred mice drastically reduce CD1d expression with consequent severe reduction in iNKT cell frequency (16).

Lipid presentation by CD1d

Central to its ability to function as an antigen-presenting molecule, surface CD1d undergoes internalization and trafficking from the cell surface to endosomal and lysosomal compartments in the cytosol. In these compartments, CD1d exchanges its ligands with glycolipids, either endogenous to the cell or acquired from exogenous sources, before returning to the cell surface to present these lipids (6).

Specifically, B cells may capture and internalize foreign lipid antigen directly through the B cell receptor (BCR), a concept that may be utilised in the design of novel lipid bound immunogens (17-19). Alternatively, B cells may, like dendritic cells, be able to capture and present ApoE/lipid complexes via the low-density lipoprotein receptor (LDLR), in a BCR-independent manner (20).

In the ensuing discussion we will highlight key studies that have helped elucidate the potential role and regulation of CD1d expression on B cells, in health and in disease. We aim to show the importance of CD1d expression on B cells for efficient humoral immune responses against pathogens and in response to vaccines. In addition, we examine how CD1d, by serving to mark development of mature B cells, might provide novel insights into the biology of autoimmune disease, EBV infection of B cells and B lineage malignancies. We suggest that a greater understanding of these processes will allow their exploitation for diagnostic, prognostic and therapeutic benefit.

CD1d in normal B cells

CD1d is expressed in mature, naïve and memory B cells, in plasma cells and also in B regulatory cells (Bregs) (14, 21). The latter are a subset of immunoregulatory, IL-10-secreting B cells that immunophenotypically correspond to recent bone marrow emigrants called transitional B cells, and are implicated in the pathogenesis of autoimmune disorders. Their role in immune regulation was recently reviewed and will not be discussed further here (21).

The humoral immune response

The B cell immune response can be categorized as T cell-independent (TI) or T cell-dependent (TD). TI responses do not require direct interaction with T helper cells (TH). They can be further classified as type 1, in which the B cell is stimulated by activating ligands (e.g. CPG) that do not engage the BCR, or type 2, in which the BCR is engaged by multivalent epitopes such as polysaccharides. TI responses generally lead to extrafollicular antibody-producing cells rather than germinal centre (GC) formation, do not generate high affinity antibodies, and produce few plasma cells and atypical memory cells (22). The result is a rapid yet transient innate-like response that does not lead to enhanced recall responses.

TD responses occur through BCR activation in the presence of cognate help from a specialized subset of CD4+ TH cells, termed T follicular helper cells (TFH) (23). TFH cells are regulated by the transcriptional repressor Bcl-6, use the chemokine receptor CXCR5 to home towards the B cell follicles, and express key molecules important for T/B cell interactions, including IL-21, PD-1, SAP, ICOS and CD40L (24). B cells consequently differentiate within the follicles, giving rise to GCs, the hallmark of the TD response. Within GCs, class-switch recombination, somatic hypermutation and affinity maturation leads to generation of high affinity Ig-secreting, long-lived plasma cells and memory cells, thus ensuring a strong anamnestic response (25).

Regulation of the humoral immune response by CD1d and iNKT cells

Similar to conventional T cells, iNKT cells can also regulate, enhance and sustain humoral immune responses. Early studies revealed that administration of α-GalCer to mice induced iNKT cell activation, led to an IL-4-dependent activation of B cells, and in some cases an increase in total serum IgE levels (26). Using iNKT cell-deficient TCRJα18−/− mice, dependency of IgE responses on iNKT cells was subsequently shown in models of allergy, such as ovalbumin-induced asthma (27). Similarly, the use of CD1d−/− mice has revealed impaired antibody responses to bacteria, including Borrelia species and Streptococcus pneumoniae polysaccharides (28, 29). More recently, it was shown that NKT cells play a critical role in the production of antibodies against the blood group A antigen (30). In comparison to wild type mice, NKT cell-deficient mice did not develop increased anti-A levels (IgM and IgG) on immunization with blood group A red blood cells. Furthermore, CD1d blockade by administration of a monoclonal antibody prior to immunization also abrogated the anti-A response, in both wild type and humanized mice.

The precise nature of the interaction between iNKT and B cells can vary, and does not always depend on CD1d expression specifically by B cells. In order to further elucidate this interaction, investigators took advantage of the adjuvant function of lipid antigens, primarily α-GalCer.

Cognate and non-cognate interactions between iNKT and B cells

The help provided by iNKT to B cells may occur indirectly through non-cognate mechanisms. This principle was demonstrated by the generation of a series of murine bone marrow radiation chimeras, lacking CD1d or CD40 on B lymphocytes, or expressing CD1d or MHC II disjointly on antigen presenting cells (APCs) (31). These experiments showed that B cell responses against nominal protein antigens could be enhanced by α-GalCer. This could occur in the absence of CD1d but not CD40 on B cells, and furthermore required co-expression of CD1d and MHC II on APCs. Taken together, the findings suggested a non-cognate mechanism for iNKT help to B cells, through licensing of APCs, increased TFH cell activation and thus improved conventional T/B cell interactions. In this role, α-GalCer is acting as a classical immunological adjuvant, stimulating early innate immune responses to aid the establishment of protective adaptive responses. This is underlined by pre-clinical studies in which vaccines containing α-GalCer mixed with protein antigens have been shown to induce more effective humoral and memory responses against several viral, parasitic and bacterial pathogens (32).

However, there is now firm evidence that B cells, through CD1d expression, are indeed able to also form cognate interactions with iNKT cells, driving a novel form of humoral immune response. First, it was demonstrated that iNKT cells in vitro promoted proliferation of autologous B-lymphocytes and induced Ig production in a CD1d-dependent manner (33). iNKT cell help to B cells could occur both in the presence or absence of α-GalCer, suggesting that B cells expressing CD1d can present exogenous or endogenous lipid to iNKT cells. Further work in MHC class II−/− mice (which lack all class II-restricted T cells) provided support for this concept in vivo. Co-administration of α-GalCer with TD antigen was able to induce a limited antibody response in mice lacking Th cells, implying that iNKT cells could act as an alternative, albeit less efficient, cognate partner for B cells (34, 35). The CD1d-restricted nature of these cognate iNKT-B cell interactions was also shown to occur in vivo. Specifically, in B cell-deficient μMT mice reconstituted with B cells from WT or CD1d−/− donors, α-GalCer enhanced antibody responses against NP-KLH, dependent on CD1d expression by B cells (36).

As a caveat, several of the studies up to this point had employed a similar immunization strategy, using a combination of protein antigens mixed with uncoupled α-GalCer. Such a combination is well suited to demonstrating the adjuvant properties of α-GalCer, but does not ensure efficient delivery to individual B cells of both the nominal antigen and the adjuvant lipid.

This was addressed by novel immunization methodologies which aimed to target glycolipid to the BCR and generate lipid-specific B cell responses, either by using NP hapten directly conjugated to α-GalCer (18) or protein antigen (hen egg lysozyme, HEL) and α-GalCer both linked to bead particles (19). In both cases, B cells activated by antigen can internalize both the antigen and the physically linked α-GalCer molecule through the BCR. Lipid can then bind to CD1d and subsequently be presented by the B cell to iNKT cells. Immunization of mice in this way was shown to produce rapid elevation in the titers of hapten- or protein-specific IgM and IgG (18, 19). These immunogenic formulations are not able to generate MHC-II restricted epitopes, ruling out a role for a cognate Th cell effect. Humoral responses were shown to be dependent, however, on the presence of iNKT cells, CD1d expression by B cells, CD40-CD40L signalling, CD80/CD86 co-stimulaton and interferon-γ production, strongly supporting a role for a cognate iNKT-B cell interaction.

This work was followed up by studies using the same immunization techniques in order to establish the longer-term outcome for B cells that have received cognate help from iNKT cells. When NP-α-GalCer was used to ensure lipid delivery specifically to B cells, the response was characterized by extrafollicular plasmablasts, GC formation, affinity maturation and a strong primary IgG response, dependent on IL-21 production by iNKT cells (37). There was however, impaired development of long-lived plasma cells and memory B cells, commensurate with a lack of an enhanced humoral memory response. Similar work involving the use of HEL-α-GalCer to induce stable iNKT-B cell cognate interactions also found evidence of IL-21 dependent GC reactions but a lack of long-lived plasma cells, memory B cells and enhanced recall responses (38). Finally, the outcomes of B cells in MHC class II−/− mice immunized with protein antigen and α-GalCer were explored (39). In this different immunization model, entailing use of mixed radiation chimeras and B cell transfer experiments, it was found that antigen-specific antibody responses occur in a CD1d- and CD40-dependent manner, suggestive of a cognate iNKT-B cell interaction. Furthermore, this was again accompanied by rapid but short-lived GC formation, and transient rather than long-lived antibody responses. Taken together, these studies suggest that the cognate interactions between CD1d-expressing B cells and iNKT cells thus generate a hybrid immune signature, termed the type 2 TD immune response, encompassing features of both the classic TD and TI responses.

Intriguingly, these studies have revealed a subset of iNKT cells recapitulating features of TFH cells, including expression of CXCR5, IL-21, PD-1 and CD28, all under control of the Bcl-6 transcriptional program (38, 39). Using inducible knockout mice, it was further shown that signaling lymphocyte activation molecule associated protein (SAP), which is essential for iNKT cell development (see below), is also critical for this cognate B cell interaction (40). Termed iNKTFH cells, these are the specialised NKT cells, which, like their T cell counterparts, are responsible for interacting with the antigen-presenting B cell and driving the immune response.

Recent in situ imaging studies have revealed that activated iNKT cells preferentially localize in the marginal zone (MZ) of the spleen, a specialized region in continuous contact with blood-borne antigens (41, 42). The MZ contains several innate and innate-like lymphocytes, including MZ B cells, which may play a prominent role in responding rapidly to TI antigens (43). It is of note that MZ B cells express high amounts of CD1d and secrete mainly IgM and IgG3, the main antibody isotypes produced in response to lipid conjugated antigen (44). Thus, it is plausible that these MZ B cells may be one of the predominant recipients of cognate iNKTFH help.

The physiological role of this type 2 TD response is not clear, as it may at first appear counterintuitive that there is rapid immune response with affinity maturation and yet this does not persist. It is possible that exposure in real life to pathogen lipid ligands may be more prolonged than that of soluble α-GalCer and thereby could sustain the presence of iNKTFH cell-dependent immune responses. Alternatively, pathogens may simultaneously stimulate both lipid and peptide B cell responses. The role of iNKTFH-dependent GC formation may therefore be to provide a rapid response by lipid-specific B cells, which, although deliberately abrogated, can provide a platform of primed GCs that can be re-used by newly activated peptide-specific B cells. A more recent study has added further complexity to this issue (45). By immunising mice with liposomal nanoparticles containing both Streptococcus pneumonia polysaccharides and α-GalCer, the authors demonstrated extrafollicular B cell proliferation, leading to a prolonged, high affinity, class-switched antibody response and a strong anamnestic response. This was dependent on CD1d expression by dendritic cells and B cells, indicating a two-step cognate process. This outcome, incongruous with the previous studies, may be explained by the use of a different antigenic formulation, since polysaccharides are able to act as type 2 TI antigens; nevertheless, it demonstrates the potential to target cognate iNKT cell help to B cells in vaccination strategies.

Downregulation of CD1d in GC B cells-mechanisms and purpose

In light of the concept that the help provided by iNKTFH cells may be purposely halted, it is notable that CD1d expression is lost from the surface of GC B cells (5). The in vivo biological mechanism and significance of this phenomenon, however, remain to be determined. It is of interest that in EBV-infected lymphoblasts, ENCODE analysis reveals that CD1d transcriptional downregulation (see below) is associated with binding of the Polycomb component EZH2 and bivalent chromatin status (i.e. co-existence of H3K4me3 and H3K27me3 marks) at the promoter of CD1d, suggestive of Polycomb-mediated transcriptional repression of CD1d in proliferating B cells (Chaudhry and Karadimitris, unpublished 2014).

Indeed, transcriptional downregulation of CD1d can be induced in proliferating B cells activated in vitro (14). CD1d downregulation was found to occur at both the cell surface and the mRNA level in response to various activating ligands including CD40L. Mechanistically, CD1d downregulation was associated with a decrease in RARα signalling, and could be reversed by agonists of this pathway, including all-trans retinoic acid (ATRA) and the specific RARα agonist AM580. Following in vitro activation, CD1d downregulation occured at 24 hours, reaching maximum effect at 5 days.

Upregulation of CD1d by AM580 predictably re-enabled lipid presentation. Following CD1d upregulation, lower doses of α-GalCer presented by B cells led to increased stimulation by iNKT cells and B cell proliferation. In contrast, higher doses of α-GalCer in fact induced an iNKT cell cytotoxic effect, leading to decreased numbers of B cells (14). It is tempting to speculate that these findings can be extended to the in vivo setting. A B cell CD1d-iNKTFH interaction in the GC, if too persistent, may similarly have the potential to induce iNKT cell cytotoxicity towards B cells. If appropriately timed, the downregulation of CD1d observed in the GC may therefore indeed exist to terminate such an interaction before it becomes disadvantageous. Given this temporal change in the pattern of CD1d expression during mature B cell ontogeny, it would be of great interest to analyse the endogenous lipid repertoire generated by naïve, GC and memory B cells and presented by CD1d in the context of a TD B cell response. Further insights on the significance of CD1d downregulation selectively in GC B cells would require a genetic approach that would ensure persistence of CD1d expression during the GC reaction.

CD1d in pathological B cells

Mature B cells are implicated in the pathogenesis of autoimmune disease such as systemic lupus erythematosus (SLE). In addition, they are targets for viral infection, especially by B cell-tropic viruses such as Epstein-Barr Virus (EBV), and for malignant transformation leading to a variety of B lineage malignancies including B cell lymphomas and multiple myeloma (MM). Accumulating evidence, reviewed below, suggests an important role of the CD1d-iNKT cell axis in these processes with potential therapeutic repercussions.

CD1d and B cells in SLE

B cell dysfunction is central to the pathogenesis of SLE, a systemic autoimmune disorder. This is highlighted by the ability of the anti-CD20 mAb Rituximab to induce clinical remissions in a substantial fraction of patients (46).

Recent work demonstrated a critical intersection of the CD1d-iNKT cell axis with B cells in health and in patients with SLE (47). Specifically, presence of CD1d-expressing B cells and their direct interaction with peripheral blood (PB) iNKT cells appears to be indispensable for the α-GalCer-dependent in vitro expansion of iNKT cells. Much of this effect is mediated by transitional B cells (i.e. CD19+CD38hiCD24hi), which express the highest levels of CD1d amongst PB B cell subsets.

Compared to healthy controls, patients with SLE have significantly lower frequency of PB iNKT cells, secreting abnormally low levels of IFNγ but high levels of IL-10. This finding correlates with considerably lower surface CD1d expression in patient than control B cells (but not monocytes), and in particular in Breg cells. Like GC B cells, loss of CD1d surface expression in SLE B cells is due, at least in part, to BCR signalling, which is increased in the disease in combination with other inflammatory stimuli such as IFN-α. Unlike the transcriptional loss observed in GC B cells, however, loss of CD1d expression in SLE is the result of an enhanced rate of CD1d internalisation in patient B cells. In patients who had a clinical response to Rituximab restoration of the PB B cell pool following their initial depletion was associated with restoration of the frequency and function of iNKT cells and expression of CD1d on B cells.

While these findings provide important insights into the mechanisms that underpin the quantitative and qualitative iNKT cell defects in SLE, the role of dysfunctional iNKT cells in the pathogenesis of SLE and indeed of autoimmune disease in general remains unclear. In pre-clinical models, activation of the CD1d-iNKT cell axis can prevent or ameliorate established autoimmune disease (48), providing impetus for development of clinical protocols that will aim to restore iNKT cell frequency and function in patients with autoimmune disorders including SLE.

CD1d and virally infected B cells

Immune evasion through downregulation of classical MHC molecules is a recognised strategy employed by viruses to withstand elimination by host defence mechanisms and help ensure their propagation (49). Highlighting the importance of CD1d in anti-viral immune responses, several viruses, including herpes viruses, have been shown to downregulate expression of CD1d in APCs through post-transcriptional mechanisms (50, 51). This raised the prospect that EBV, a ubiquitous human herpes virus that targets B cells (52), could employ a similar strategy.

EBV has initial tropism for pharyngeal epithelial cells, but then spreads to local naïve B cells (via surface CD21 and HLA class II molecules) within tonsillar lymphoid tissue. Currently accepted models of chronic EBV infection propose that in order to persist in the host, EBV infects naïve B cells and drives B cell maturation through a GC-type reaction in order to produce memory B cells in which the virus can reside latently long term (52). EBV achieves this through expression of different genetic latency programmes (0-III) in different B cell subsets, associated with the transcription of different viral proteins, notably of LMP1 and LMP2a (53, 54).

It is possible that the imitation of the process of GC formation, and the consequent drastic downregulation of CD1d in EBV-infected cells, confers protection to the virus-propagating B cells from iNKT cell attack. Indeed, evidence from the study of patients with X-linked lymphoproliferative disorder (XLP) caused by mutations in SH2D1A/SAP or XIAP, further suggests that the CD1d-iNKT axis might be important in restraining EBV into a latent state. Individuals with XLP, in addition to other immune function defects, have profound defects in iNKT cell development associated with active EBV replication and EBV-associated lymphoproliferation (55, 56).

Following on from these observations, the nature of the interaction between EBV infected B cells and NKT cells was examined in vitro (15). It was demonstrated that EBV infection of resting B cells can be mitigated by the presence of iNKT cells, indicating that EBV infected B cells are indeed a target for NKT cells. However, in a parallel to the physiological activation of B cells, EBV infection of B cells rapidly leads to loss of expression of CD1d, abrogating further interaction with NKT cells and thus providing a form of immune evasion. Similarly, like their physiologically activated counterparts, CD1d expression in EBV infected B cells in vitro could be restored by a RARα agonist, re-enabling the stimulation and cytotoxic effects of NKT cells, even in the absence of exogenous antigen (15).

Downregulation of CD1d expression by EBV occurs at the transcriptional level, as opposed to post-transcriptional mechanisms employed by other viruses. Using chromatin immunoprecipitation, it was shown that transcriptional repression of CD1d in B cells occurs through binding of the LEF-1/β-catenin complex (members of the Wnt pathway) to the CD1d distal promoter upon EBV infection and that treatment with AM580 restores CD1d expression by inhibiting binding of LEF-1 in this region.

CD1d and malignant B cells

Numerous pre-clinical studies have demonstrated the power of the CD1d-iNKT cell axis to enhance (or in some cases inhibit) anti-tumour immunity (57). iNKT cells can directly target CD1d-expressing tumours (mostly of haematological, including lymphoid origin) (58, 59), or indirectly, by activating adaptive and innate immune responses that can secondarily target CD1d- tumours (mostly of epithelial origin). Here we will restrict discussion to the evidence linking the CD1d-iNKT cell axis to the biology and clinical behaviour of mature B lineage malignancies, in particular MM and chronic lymphocytic leukaemia (CLL), two of the most common haematological malignancies.

Multiple myeloma

MM is a malignant monoclonal plasma cell disorder characterized by end-organ damage including anaemia, hypercalcemia, renal insufficiency and bone lesions (60).

CD1d is dynamically downregulated on myeloma plasma cells during disease progression (61). Specifically, in primary myeloma samples, CD1d was highly expressed in pre-malignant and early stage disease, but was decreased, and subsequently lost, in advanced stage MM. Similarly, loss of CD1d expression was observed in most myeloma cell lines, both in terms of surface and mRNA expression, thus implicating this molecule as an important anti-survival factor in MM. These observations suggest that loss of CD1d is advantageous for the propagation of the malignant clone and permits evasion of myeloma cells from iNKT cell-mediated immune surveillance, a process that would be further undermined by the defective (but reversible) production by iNKT cells of IFN-γ in patients with progressive disease (62).

However, in addition to immune escape, CD1d may also act as a signalling conduit in myeloma cells. In myeloma cell lines with restored expression of CD1d, ligation of surface CD1d by mAb induced caspase-independent apoptosis (an effect dependent on the cytoplasmic tail of CD1d but not the Tyr residue required for endosomal trafficking of CD1d) (61, 63). Thus, loss of CD1d may also be important in that it allows myeloma cells to avoid the triggering of CD1d-dependent, downstream anti-survival signalling pathways.

The therapeutic potential of the CD1d-iNKT cell axis was explored in a phase I trial in which autologous myeloid DCs loaded with α-GalCer were infused into patients with indolent myeloma (64). The procedure was safe and was associated with significant reduction of paraprotein level, indicating anti-myeloma activity. Notably, this small cohort of patients was also treated with lenalidomide, which had been previously found to enhance iNKT cell function in patients with myeloma.

B-cell chronic lymphoproliferative disorders

B-cell chronic lymphoproliferative disorders (B-CLPDs) are a heterogeneous group of diseases arising from the clonal expansion of mature B cells at different stages of differentiation (65). Immunophenotypic analysis of surface markers plays a key role in both the diagnosis and prognostication of B-CLPDs, especially CLL, and thus several studies have examined the potential of CD1d to be utilised in such a manner.

Several studies, each involving over 100 patients, found that surface expression of CD1d is significantly, although variably, downregulated in CLL compared with other B-CLPDs, and is lower than in normal B cells; CD1d expression levels below a set threshold are strongly predictive of CLL and higher CD1d expression levels are associated with reduced time to treatment and overall survival (66-68).

CD1d expression was also associated with several other known poor prognostic markers in CLL, including expression of ZAP-70, CD38 and CD49d, unmutated IgVH status and cytogenetic abnormalities (67-69). However, whether CD1d is a surrogate or an independent prognostic marker remains to be established. The latter would be more significant and would suggest that the CD1d molecule may actually play a direct role in the pathobiology of the disease. This concept is also strengthened by the observation that CD1d expression in CLL, like myeloma, is dynamic, and changes during disease progression (68). However, while CD1d expression in myeloma decreases as disease progresses, CD1d expression in CLL cells tends to increase during disease progression. This may appear counter to the postulated role of CD1d as an anti-survival factor in myeloma. It is possible that the presence of CD1d provides downstream signals that are advantageous to the malignant CLL B cells. Alternatively, increased expression of CD1d may facilitate presentation of endogenous or exogenous lipids, possibly specific to the leukaemic clone, leading to cognate interactions with iNKT cells that would promote rather than inhibit survival of the leukaemic cell. This would chime well with the observation that the cognate B-iNKT cell interaction, in the presence of endogenous or low concentration of exogenous glycolipid ligand, promotes B cell proliferation in vitro (33), and with the finding that, unlike in MM, iNKT cells in CLL are fully functional (70).

In contrast to CLL, CD1d is highly expressed in other B-CLPDs such as splenic marginal zone lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma and variant hairy cell leukaemia (66). With the exception of hairy cell leukaemia, these are largely incurable B cell malignancies and their high expression of surface CD1d would make them suitable targets for iNKT cell-based immunotherapeutic approaches.

Conclusions

CD1d exhibits dynamic expression on B cells in both health and disease, and a greater understanding of these processes will provide a platform for therapeutic opportunities (Fig. 1). Although current experimental evidence suggests an important role of CD1d and iNKT cells in the development of protective humoral immunity against pathogens, more work is required to better define their role in this context. By contrast, the pre-clinical data demonstrating B cells as the direct or indirect effectors of the potent adjuvant activity of the CD1d-iNKT cell axis are sufficiently convincing to justify development of protocols aiming to enhance vaccine efficacy in the clinical setting.

Figure 1. Dynamic expression and role of CD1d on B cells in health and disease.

Figure 1

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Expression of CD1d on normal naïve B cells permits their cognate interaction with iNKT cells. This leads to the development of the type 2 TD immune response, followed by CD1d downregulation in the germinal centre. Pathological B cells in SLE, EBV infection or in B lineage malignancy display abnormal CD1d expression. Transcriptional regulation of CD1d in these cells may also involve utilisation of physiological transcriptional pathways. Yellow highlighted boxes describe areas that warrant further research and blue highlighted boxes describe potential therapeutic strategies.

High levels of CD1d expression by certain types of B lineage malignancies makes them suitable targets for iNKT cell-based immunotherapeutic approaches, including adoptive transfer of in vitro expanded autologous iNKT cells or even chimaeric antigen receptor-modified iNKT cells targeting the B cell-specific CD19 antigen. Furthermore, the emerging evidence suggests that regulation of CD1d expression during viral infection and malignant transformation reflects its regulation during late B cell development. The reversible nature of CD1d expression regulated by the differential activity of the RA pathway points to therapeutic approaches in B lineage malignancies (including those driven by EBV) that could combine iNKT cell-based cellular therapies with biological agents such as ATRA.

Acknowledgements

We thank the members of our lab for critical reading of this manuscript.

Source of support: This work was supported by the Wellcome Trust.

Abbreviations used in this article

iNKT

invariant NKT

α-GalCer

α-galactosylceramide

TI

T cell-independent

TD

T cell-dependent

GC

germinal centre

EBV

Epstein-Barr Virus

MM

multiple myeloma

CLL

chronic lymphocytic leukaemia

Footnotes

Disclosures

The authors have no financial conflicts of interest.

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