Investigating the signals that regulate the function of dendritic cells (DC), the sentinels of the immune system, is critical to understanding the role of DC in the regulation of immune responses. Accumulating lines of evidence indicate that in addition to innate stimuli and T cell-derived signals, B lymphocytes exert a profound regulatory effect in vitro and in vivo on the Ag-presenting function of DC. The identification of B cells as a cellular source of cytokines, chemokines, and autoantibodies that are critically involved in the process of maturation, migration, and function of DC provides a rationale for immunotherapeutic intervention of autoimmune and inflammatory conditions by targeting B cells. Conversely, efficient cross-presentation of Ags by DC pulsed with immune complexes provides an alternative approach in the immunotherapy of cancer and infectious diseases.

The specificity, magnitude, and outcome of an immune response are largely determined at the stage of Ag presentation by APC such as dendritic cells (DC)3, B lymphocytes, and macrophages. DC are at the crossroads of innate and adaptive immunity and have a prominent role both in the initiation of the primary immune response and in the induction of immune tolerance through interaction with T and B lymphocytes. To acquire T cell stimulatory ability, DC must undergo maturation, which involves up-regulation of surface MHC class II and of costimulatory molecules, expression of immunoregulatory cytokines, and migration into T cell areas of secondary lymphoid tissues. In addition to T cell stimulation, DC also regulate B cell growth and secretion of Igs (for review, see Ref. 1).

Investigating signals that initiate and regulate the differentiation, maturation and activation of DC is critical for understanding the role of DC in immune homeostasis, and for developing methods to manipulate the immune system for vaccination and therapy. Innate stimuli and T cell-derived signals are considered to be the main factors controlling the maturation and function of DC. However, several recent reports have emphasized that B lymphocytes also monitor maturation and function of DC, thus providing a new twist in the tale of the “ménage à trois” of DC-T-B lymphocytes. An overview of the recent results discussed herein reveals several different mechanisms through which B cells scrutinize the function of DC.

CD11c+ splenic DC from B cell-deficient (μMT) mice produce higher levels of IL-12 upon CD40 stimulation and display an impaired ability to induce IL-4 secretion from Th cells, most likely due to decreased levels of IL-10 from splenocytes (2, 3). Pulsing splenic DC from μMT mice with keyhole limpet hemocyanin followed by injection of cells into wild-type mice induced the differentiation of Th cells secreting IL-2, IFN-γ, IL-5, and IL-10 but no detectable IL-4, whereas priming with DC from control mice led to IL-4 production in addition to other cytokines (2). Of particular interest, splenic DC from IL-10 knockout mice displayed properties similar to DC from μMT mice, and treatment of DC from μMT mice with IL-10 restored the generation of IL-4-producing cells in vivo (2). Similarly, a preferential Th1 profile of response was also observed in patients with X-linked (Bruton’s) agammaglobulinemia (XLA) who lack peripheral circulating B lymphocytes due to Btk mutations (4).

Collectively, these observations suggest that the level of IL-12 production by DC and the onset of Th2 response are regulated by B lymphocytes or by opsonizing Abs, probably by promoting the production of IL-10. Furthermore, B cell-derived IL-10 was proposed to play a role in oral tolerance by enhancing the tolerogenic capacity of DC in the GALT of mice (5). A report by Skok et al. (6) suggests a feedback loop triggered by splenic DC-derived IL-12 that promotes Th2 differentiation. Delivery of IL-12 by CD11c+ splenic DC during B cell activation induces the secretion of IL-6 and IL-10 by activated B cells. IL-6 and IL-10 in turn confer on these B lymphocytes the capacity to induce IL-4 expression in T cells. Thus, these reports indicate that a bidirectional regulation occurs upon DC-B cell interaction.

IL-16 is a polypeptide cytokine that was originally described as a T cell-specific chemoattractant factor. As a natural soluble ligand for CD4, it has been shown to induce chemotaxis of CD4+ T cells as well as of monocytes, eosinophils, and monocyte-derived DC (Mo-DC) in humans (7). Kaser et al. (8) demonstrated that human CD19+ B lymphocytes constitutively express IL-16 mRNA and synthesize bioactive IL-16 protein. IL-16 from unstimulated B lymphocytes efficiently induced the migration of human Mo-DC and of circulating CD4+CD11c+ blood DC. Furthermore, neutralization of B cell-derived IL-16 bioactivity strongly inhibited this migratory response, suggesting that IL-16 was a major chemotactic factor derived from B cells in a steady state (8). Stimulation of B cells did not change the level of IL-16 production (8). However, neutralization of activated B cell-derived IL-16 inhibited the migration of Mo-DC only up to 62%, a finding consistent with the fact that activated B cells also provide other survival or maturation signals and/or chemoattractant factors for DC (9, 10, 11, 12).

Overall, these data support the idea that IL-16 might have a role in the initiation of cellular, as well as humoral immunity, by mediating cellular cross-talk among CD4+ Th cells, B cells, and DC, leading to recruitment of these cell types to common anatomical sites. These findings may also explain the consistent reduction in the number of splenic DC in B cell-deprived mice as compared with wild-type animals (2, 11).

B cell-derived membrane lymphotoxin has been found to be essential for regulating the migration of a murine CXCR5+CD11c+ subset of DC into the spleen by controlling CXCL13 expression on LTβR-expressing follicular stromal cells (13, 14). In contrast, although splenic expression of CCL21 (a ligand for CCR7 and expressed by mature migrating DC) is dependent on the B cell-derived lymphotoxin, it is unlikely that B cells influence the number of DC in the spleen through CCL21 or CCL19, because mice that lack these chemokines in lymphoid tissues were found to have normal numbers of spleen DC (15, 16). However, it remains possible that B cells promote homing of DC to the spleen through their secretion of other chemokines/cytokines, e.g., MIP-1α and MIP-1β or other factors (8, 9, 10, 11, 12).

Various subsets of human and mouse DC express functional FcR: FcγR, FcαR, and FcεR. In the mouse, bone marrow-derived DC, splenic DC, and Langerhans cells (LC) express FcγRI (CD64), FcγRIII (CD16), and FcγRIIB (CD32) (17, 18, 19, 20), whereas LC also express FcεRII (21). Of note, FcγR expression is observed on resident LC in vivo/in situ but not on in vitro-generated, cytokine-derived LC. In humans, Mo-DC express mainly FcγRII (both A and B isoforms), FcαRI (CD89), and transferrin receptor (CD71) (22, 23, 24, 25, 26), LC express FcγRII and FcεRI (27, 28, 29, 30, 31, 32, 33, 34, 35), and blood DC express FcγRII, FcγRI, and FcεRI (36, 37, 38, 39). Mo-DC also express the neonatal MHC class I-like FcR for IgG (40).

DC can be activated or inhibited through FcR by Abs or IC formed by Abs depending on the kind of FcR engaged. Two general classes of FcγR exist on DC: activating receptors (FcγRI, FcγRIIA, and FcγRIIIA) and an inhibitory receptor (FcγRIIB). The activating receptors are characterized by the presence of a cytoplasmic ITAM. Tyrosine phosphorylation of this motif may initiate maturation of DC, and glycosyl phosphatidylinositol (GPI)-anchored proteins are indispensable for tyrosine phosphorylation of FcγR in myeloid CD11c+CD11b+ splenic DC (41). The inhibitory receptor is characterized by the presence of an ITIM, which inhibits ITAM-mediated activation signals through the recruitment of the inositol-phosphatase SHIP (42, 43). Thus, the FcγR system represents a balance of activating and inhibitory receptors that determines the outcome of IC-mediated signaling in target cells (Fig. 1).

FIGURE 1.

A schematic representation of monitoring of DC maturation and function by B lymphocytes.

FIGURE 1.

A schematic representation of monitoring of DC maturation and function by B lymphocytes.

Close modal

It should also be borne in mind that the FcγR system differs significantly between mice and humans, in both the number and type of activating and inhibitory receptors. This difference may complicate the translation of data generated in mice to humans. Although in mice several subsets of DC have been studied in detail for FcR function, studies of human FcR are largely restricted to Mo-DC. In addition, the pattern of FcγR expression in vivo, in DC subsets, or during maturation is still unclear. Human Mo-DC express both activating and inhibitory isoforms of FcγRII, mouse DC express only FcγRIIB but lack FcγRIIA (44). Although the expression of FcγRIIB accounts for ∼75% of total FcγR expression on mouse bone marrow-derived DC (19), other activating FcγR may compensate for the lack of FcγRIIA in mice.

Perhaps for these reasons, investigations into the effects of FcR signaling on DC have yielded conflicting results. Although, several reports demonstrated maturation of DC upon engagement of most FcR by IC (18, 24, 33, 45), other studies have shown that human Mo-DC are not induced to mature or become activated after FcγR engagement (46, 47, 48). Heterogeneous expression of activation and inhibitory FcγR in different DC populations could account for these discrepancies.

Interestingly, as reported recently, a selective blockade of inhibitory FcγR can also lead to the maturation of human Mo-DC (26). This supports the hypothesis that the balance between activation and inhibitory FcγR on DC is critical to induce their maturation and that interfering with the inhibitory signal delivered by FcγRIIB enhances the ability of IC to induce maturation of DC (19). Several factors, including FcγR polymorphism and cytokines, can affect the relative expression of activation and inhibitory receptors and the net effect of FcγR engagement (49, 50). In addition, different Ig subtypes may vary in the extent to which they induce maturation. Mouse IgG2b Abs induce maturation of the long-term, cultured, growth factor-dependent H-2b splenic DC cell line D1 but are less potent than IgG1 in the induction of IL-12 (51).

Cross-linking of FcγRII with immobilized IgG induces the maturation of human Mo-DC via the NF-κB signaling pathway (52). Similarly, engagement of FcεRI in human LC induces activation of the NF-κB pathway, phosphorylation of the tyrosine kinase Syk, and mobilization of Ca++ (33, 53). FcγR engagement in mouse bone-marrow-derived DC induces phosphorylation of Syk and ERK, and Syk is indispensable for IC-induced maturation of DC and Ag presentation (54, 55).

FcR-mediated uptake of IC promotes efficient MHC class I, as well as class II-restricted Ag presentation, by various DC subsets both in humans (myeloid and blood DC) and mice (bone marrow-derived and splenic DC) and dramatically lowers the dose of Ag required for T cell activation (18, 56, 57, 58, 59, 60, 61). Cross-presentation was shown to occur at >1000-fold lower concentration of Ag for FcγR-mediated vs fluid phase uptake of Ag by mouse bone marrow-derived and splenic DC (18, 62). This cross-presentation pathway is dependent strictly on IC receptors because DC from receptor-deficient mice failed to cross-present IC efficiently (18). Furthermore, cross-presentation by the CD8 subset of murine splenic DC is dependent on the expression of γ-chain containing activating FcγR, whereas cross-presentation by CD8+ DC is not (59), thus implying constitutive cross-presentation by CD8+ DC.

FcγRIII and FcγRII are also critical for tumor-directed Ab-dependent cellular cytotoxicity by the M-DC8+ subpopulation of circulating human blood DC (63), a subset of DC that was identified by reactivity to mAb M-DC8 and by characteristic expression of FcγRIII; these cells account for 1–2% of PBMC (64).

FcR-mediated uptake and presentation of Ag through IC are implicated in several pathological conditions. Cross-linking of FcγRII by lupus-IgG induces the maturation of human Mo-DC via NF-κB signaling (52). Similarly, chromatin-IC activates murine bone marrow-derived myeloid CD11c+CD11b+ DC by two distinct pathways (65). One of these involves dual engagement of the FcR FcγRIII and TLR9, whereas the other is TLR9 independent. Interestingly, activation of bone marrow-derived DC by chromatin-IC elicited a characteristic cytokine profile as compared with conventional TLR ligands in that chromatin IC induced B cell-activating factor from the TNF family but not IL-12 (65).

Cross-linking of FcγR on human plasmacytoid DC by IC-containing lupus-IgG and nucleic acid (DNA and RNA) released by either necrotic or late apoptotic cells was shown to stimulate the production of IFN-α (66, 67, 68, 69, 70, 71). This IFN-α-inducing activity of IC formed by lupus-IgG involves a cooperative interaction between TLR9 and FcγRIIa (71) and is dependent on the Fc portion of the IgG because the Fab or F(ab′)2 of lupus-IgG were shown to be inactive (69). The presence of such stimulatory IC could explain the ongoing production of IFN-α in lupus and might be of importance in the pathogenesis of systemic lupus erythematosus.

IC formed by the soluble E2 component of pyruvate dehydrogenase (PDC-E2) and affinity-purified autoantibodies against PDC-E2 from patients with primary biliary cirrhosis induce the generation of PDC-E2-specific CTLs at a 10-fold lower concentration than soluble Ag alone (47). The finding that autoantigen-IC not only can cross-present the autoantigens but also present them with a higher relative efficiency defines a unique role for disease-associated autoantibodies in the pathogenesis of autoimmune diseases.

FcεR-mediated uptake of IgE-associated allergens plays a pivotal role in the pathogenesis of allergic diseases that may critically lower the threshold of atopic individuals to mount allergen-specific T cell responses. In humans, FcεRI occurs as a multimeric structure containing the intracellular α-chain of the FcεRI (FcεRIα) and γ-chains of the FcεRI (FcεRIγ). However, expression of the FcεRIγ-chain is mandatory for surface expression of FcεRI. Mo-DC and LC from healthy donors express intracellular FcεRIα-chain but are low or negative for FcεRIγ-chain and hence lack surface expression of FcεRI (with an exception being in peripheral blood DC, wherein the expression of FcεRI is similar in both healthy as well as atopic asthmatic subjects) (72, 73).

In contrast, expression of FcεRIγ-chain, FcεRI, and FcεR-bound IgE was found to be significantly greater on LC, blood DC subsets, and Mo-DC in atopic and allergic manifestations that can lead to biologically important changes in the function of DC such as enhancement in their capacity to induce proliferation of autologous T cells (35, 39, 72, 73). Ligation of FcεRI on Mo-DC by IgE can also lead to the production of TNF-α, MCP-1, and IL-16 (53, 74), which may enhance the local inflammation by attracting effector cells. In addition, IgE can promote optimal sensitization in contact sensitivity by enhancing the expression of mast cell-associated mediators such as TNF-α, IL-1β, IL-6, mouse mast cell protease-6, and MCP-1 in an Ag-nonspecific fashion (75) that contribute to the migration of DC.

The identification of FcR-mediated maturation and efficient MHC class I- and class II-restricted Ag presentation by DC and its role in the development of an effective Th1 response against intracellular pathogens provide a rationale for novel immunotherapeutic approaches to treating cancer and infectious diseases (19, 45, 60, 61, 76, 77, 78, 79, 80). Bone marrow-derived DC loaded with IC have been shown to induce antitumoral CD4+ and CD8+ CTL responses and full tumor protection in vivo in murine models of melanoma and thymoma (19, 78).

Abs that bind to surface molecules on specific cell types are present in the steady state. Such Abs, also known as natural Abs (NAbs), are an integral part of the normal Ig repertoire and are not elicited by deliberate immunization. NAbs are the products of germline Ig gene expression in B cells that are positively selected during ontogeny (81). The majority of NAbs exhibit autoreactivity and are proposed to participate in the maintenance of immune homeostasis under physiological conditions (82). NAbs that bind to CD40 and B7-DC and that evoke important biological changes in the DC have been identified recently (Fig. 1).

To assess the importance of NAbs on human Mo-DC development, we have examined the differentiation of Mo-DC in patients with XLA, a disease characterized by a paucity of B cells and of circulating Abs, and in patients with common variable immunodeficiency, a disease characterized by hypogammaglobulinemia and defective T and B cell functions. We demonstrated that the differentiation of Mo-DC is impaired severely in these patients, at least in part due to low levels of circulating NAbs, although genetic defects and T cell defects might also contribute to the defects of Mo-DC in common variable immunodeficiency patients (Refs. 83 and 84 ; J. Bayry, O. Hermine, and S. V. Kaveri, unpublished observations).

We identified NAbs reactive with CD40 as an important component of the human Ig repertoire that participate in the development of Mo-DC (83). CD40-reactive NAbs restored normal phenotypes to Mo-DC from XLA patients. The maturation process induced by CD40-reactive NAbs was accompanied by increased IL-10 and decreased IL-12 production and activation of the CREB-1 pathway. The fact that signaling by the NAbs does not initiate IL-12 production makes teleological sense because it ensures that maturation of DC does not lead to Th1 differentiation by default. The results are consistent with previous observations made in μMT mice, wherein opsonized Abs promote IL-10 secretion from splenic DC (2, 3). Thus, the lack of induction of IL-10 associated with the lack of stimulation by NAbs (or B cells) may, in the context of efficient CD40L signaling and IL-12 production, participate in the development of pathological Th1 responses in patients with XLA (4).

In contrast, natural IgM Abs (sHIgM12) that bind B7-DC, one of the B7 superfamily members on DC, dramatically potentiated the ability of the bone marrow-derived DC to activate naive T cells to a Th1 phenotype by a STAT4-dependent pathway (85, 86, 87). The authors hypothesized that these Abs enhance DC function by stimulating up-regulation of cell surface molecules, by inducing secretion of factors that influence T cell activation, and/or by boosting DC survival (85, 86, 87). Monomeric fragments of the sHIgM12 Ab did not potentiate the immune response of bone marrow-derived DC and were able to block the ability of intact pentamer to do so (85). Pentamers are well known for their low-affinity reactivity with Ags that have repeating structural motifs. The availability of 10 identical binding sites on pentameric IgM Abs provides an increase in avidity that compensates for low affinity in generating measurable interactions between the Abs and their ligands. Targeted cell surface molecules function as repeating epitopes because they can become juxtaposed in the dynamic membrane. Therefore, the pentameric structure also allows for cross-linking of cell surface molecules, an event often associated with the initiation of signaling cascades (85, 86, 87).

Taken together, these results indicate that NAbs with various specificities, which are potentially important biological agents, are prevalent in the healthy immune repertoire. However, the functional outcome of these interactions is determined by the affinity and isotype of Abs, the epitopes they recognize, and their concentration. The identification of NAbs that modulate the functions of DC have potential clinical ramifications in the immunotherapy of autoimmune and inflammatory conditions and cancer (86, 87).

IVIg is a therapeutic Ig preparation obtained from pools of plasma from a large number of healthy blood donors (88). As a consequence, NAbs are essential components of IVIg. IVIg has been found to be beneficial in a variety of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. IVIg inhibits the differentiation and maturation of human Mo-DC and abrogates the capacity of mature DC to secrete IL-12 while enhancing IL-10 production (89, 90). IVIg-induced down-regulation of costimulatory molecules and modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T cell activation and proliferation (Fig. 1). The results point toward a therapeutic use of normal circulating NAbs through targeting DC.

Accumulating evidence indicates that B cell function may not be exclusively limited to Ab production. The results discussed here imply that B lymphocytes have a profound regulatory effect on the Ag-presenting function of DC in vitro and in vivo. Indeed, DC from B cell-deprived animals have an impaired capacity to induce Ag-specific differentiation of IL-4-secreting T cells. Therefore, B cells may directly, or indirectly via interaction of NAbs/opsonizing Abs, favor the development of Th2-type cells that provide helper activity for Ab synthesis, thereby promoting their own effector function. B cells may also actively create a lymphoid microenvironment that promotes their interaction with other cells in orchestrating efficient IgG responses by a constant cross-talk with DC and T cells.

The importance of NAbs reactive with self-Ags has long been neglected because tolerance to self was thought to be primarily dependent on the deletion of autoreactive clones during ontogeny. However, it is now well established that autoreactive Abs and B and T cells are present in healthy individuals. Although several functions have been postulated for NAbs under physiological conditions, a role for NAbs in DC-mediated immune homeostasis has not been investigated until recently. The identification of NAbs reacting with several immunologically relevant molecules should kindle additional research on understanding the interplay between NAbs and DC. The fact that NAbs are essential components of therapeutic IVIg that is already in use for treating a wide range of autoimmune and inflammatory conditions suggests that receptor-specific NAbs may be of therapeutic importance for selected immune disorders.

Finally, identifying B cells as a cellular source of cytokines and chemokines, which are critically involved in the process of DC migration, or as a producer of autoantibodies in autoimmune diseases, which augment the inflammatory process via ligation of FcR on DC, provides a rationale for immunotherapeutic intervention by targeting B cells (91). In contrast, efficient cross-presentation of Ag by DC pulsed with IC underlines a basis for an alternative approach in the immunotherapy of cancer and infectious diseases (19, 78).

We are grateful to Chris G. F. Mueller, Agnes Le Bon, and Rob Carter for critical reading of the manuscript. Because of space limitations, we were only able to cite key references but acknowledge the key contributions to the field of numerous uncited studies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

This work is supported by grants from the Edward Jenner Institute for Vaccine Research, U.K. (to J.B., D.F.T.), the Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique, France (to S.L.-D., M.D.K., O.H., S.V.K.), the Laboratoire Français du Fractionnement et des Biotechnologies, Les Ulis, France, Octapharma, Austria, and ZLB Behring, Switzerland (to S.L.-D., M.D.K., S.V.K.).

3

Abbreviations used in this paper: DC, dendritic cell; XLA, X-linked agammaglobulinemia; Mo-DC, monocyte-derived DC; LC, Langerhans cell; IC, immune complex; PDC-E2, E2 component of pyruvate dehydrogenase; NAbs, natural Abs; IVIg, i.v. Ig.

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