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. Author manuscript; available in PMC: 2018 Aug 15.
Published in final edited form as: Immunity. 2017 Aug 15;47(2):224–233. doi: 10.1016/j.immuni.2017.07.009

Fcγ Receptor Function and the Design of Vaccination Strategies

Stylianos Bournazos 1, Jeffrey V Ravetch 1,*
PMCID: PMC5573140  NIHMSID: NIHMS894407  PMID: 28813656

Abstract

Through specific interactions with distinct types of Fcγ receptors (FcγRs), the Fc domain of IgG mediates a wide spectrum of immunological functions that influence both innate and adaptive responses. Recent studies indicate that IgG Fc-FcγR interactions are dynamically regulated during an immune response through the control of the Fc-associated glycan structure and Ig subclass composition, on the one hand, and selective FcγR expression on immune cells on the other, which together determine the capacity of IgG to interact in a cell type specific manner with specific members of the FcγR family. Here we present a framework that synthesizes the current understanding of the contribution of FcγR pathways to the induction and regulation of antibody and T-cell responses. Within this context, we discuss vaccination strategies to elicit broad and potent immune responses based on the immunomodulatory properties of Fc-FcγR interactions.

Introduction

Remarkable technical and scientific advances in hybridoma technologies during the last decades of the previous century facilitated the development of highly specific monoclonal antibodies (mAbs), culminating in the approval of the anti-CD3 mAb muronomab, as the first mAb for clinical use in humans. Since then, the US Food and Drug administration (FDA) has approved over 65 mAbs for the treatment or management of neoplastic, chronic inflammatory, autoimmune, and infectious diseases. These mAbs and mAb-based biologics have revolutionized our therapeutic approaches for a number of diseases and their widespread clinical use has been characterized by unsurpassed efficacy and safety. Currently there are over a few hundreds of mAbs in clinical trials and it is expected that within the next decade mAb-based therapeutics will become the mainstream treatment approach for neoplastic diseases. Depending on the antigen targeted and the desired clinical outcome, mAbs mediate therapeutic activities through diverse mechanisms. For example, cytotoxic antibodies against lymphoma and tumor cells induce the therapeutic elimination of malignant cells, whereas checkpoint inhibitor antibodies mediate antitumor activity through their immunomodulatory function to alter the composition and the functional activity of leukocytes within the tumor microenvironment. In contrast, mAbs approved for the control of chronic inflammatory and autoimmune pathologies directly target key inflammatory pathways, such as tumor necrosis factor (TNF)-α, interleukins and interleukin receptors. Likewise, mAbs against infectious diseases such as respiratory syncytial virus (RSV), Ebola, HIV-1, and Anthrax, mediate protective activity through neutralization of foreign antigens and/or elimination of infected cells (Bournazos et al., 2014a; Bournazos et al., 2014b; Lu et al., 2016).

Despite the different mechanisms of action of therapeutic mAbs, a function common to all mAbs is their capacity to interact with specialized receptors (Fcγ receptors; FcγRs) expressed on the surface of leukocytes through their Fc domain. Fc-FcγR interactions represent a key component of the in vivo activity of therapeutic mAbs and have the capacity to initiate a number of diverse immunomodulatory functions that readily affect several aspects of innate and adaptive immunity. Such functions include cellular activation and the release of chemokines and cytokines by innate effector leukocytes, antigen uptake, processing and presentation by antigen-presenting cells, regulation of B cell selection and IgG production, as well as modulation of T cell activation (Bournazos and Ravetch, 2015). Given the critical role of FcγR-mediated pathways to efficiently modulate adaptive immune responses, immune complex-based vaccination strategies have been previously employed to enhance the host immune responses against infectious agents and tumor antigens (Wen et al., 2016). Indeed, the concept of IgG-mediated enhancement of T-cell and antibody responses has been initially studied during the end of the 19th century to enhance the immune responses against diphtheria (von Behring and Wernicke, 1892). Since then, a number of studies have reported that immunization with IgG immune complexes increased the immunogenicity of several antigens, including hepatitis B virus, Venezuela equine encephalitis virus, Newcastle disease virus, infectious bursal disease virus and HIV-1 (Bouige et al., 1996; Bouige et al., 1990; Haddad et al., 1997; Hioe et al., 2009; Kumar et al., 2011; Kumar et al., 2013; Pokric et al., 1993; Visciano et al., 2008; Xu et al., 2005; Xu et al., 2013; Yao et al., 2007); a concept that has also been evaluated in phase III clinical trials of immune complex-based hepatitis B vaccination protocols (Xu et al., 2013). Likewise, passive administration of therapeutic mAbs to patients or to animal disease models is often accompanied by the modulation of host immune responses against several tumor types and HIV-1 (Abes et al., 2010; Barouch et al., 2013; de Bono et al., 2004; Haigwood et al., 2004; Hilchey et al., 2009; Kwak et al., 1992; Ng et al., 2010; Schoofs et al., 2016; Taylor et al., 2007).

These studies highlight the capacity of antibodies to augment adaptive immune responses; however, the underlying mechanisms have not been systematically evaluated and the precise requirements for FcγR-mediated pathways have not been characterized. Without clear insights into the regulatory mechanisms involved in the IgG-mediated modulation of adaptive immune responses, the activity of mAb therapeutics cannot be fully exploited to provide their maximal clinical benefit. However, recent development of animal models that faithfully recapitulate the unique complexity of human FcγR biology have facilitated mechanistic studies into the immunomodulatory pathways that control cellular and humoral immune responses (DiLillo and Ravetch, 2015; Smith et al., 2012; Wang et al., 2015). The better understanding of the exact FcγR-mediated pathways involved during the induction of T-cell and IgG responses can provide the basis for novel vaccination strategies and for the modification of mAb therapeutics to provide long-lasting effects.

Here we review recent findings on the dynamic regulation of IgG Fc-FcγR interactions during an immune response, discussing these in the broader context of FcγR biology. We present a framework that synthesizes the current understanding of the contribution of FcγR pathways to the induction and regulation of antibody and T-cell responses, and discuss how this understanding translates into vaccination strategies to elicit broad and potent immune responses based on the immunomodulatory properties of Fc-FcγR interactions.

Overview of FcγR Biology

FcγRs are broadly divided into two main types - type I and type II - based on their binding stoichiometry and interaction sites with the Fc domain of IgG (Pincetic et al., 2014; Sondermann et al., 2013). Each FcγR type comprises several members with distinct immunomodulatory activity. Type I FcγRs are structurally and functionally related to the immunoglobulin (Ig) receptor superfamily, as their extracellular, IgG binding region consists of two or three Ig domains. These domains participate in the interaction with the Fc domain of the IgG, engaging the hinge-proximal region of CH2 in a 1:1 stoichiometric complex (Shields et al., 2001; Sondermann et al., 2000). Apart from the extracellular region, type I FcγRs also share highly conserved intracellular signaling domains that mediate downstream effector functions upon receptor crosslinking. Based on the signaling motifs at their intracellular domain, type I FcγRs are divided into activating or inhibitory (Nimmerjahn and Ravetch, 2005). Activating type I FcγRs include FcγRI, FcγRIIa, FcγRIIc, and FcγRIIIa and encompass immunoreceptor tyrosine activation motifs (ITAM) present either at the intracellular domain of FcγR (for FcγRIIa and FcγRIIc) or at the associated FcR γ chain, which is required for the expression and signaling of FcγRI and FcγRIIIa (Amigorena et al., 1992; Swanson and Hoppe, 2004; Takai et al., 1994). The sole inhibitory type I FcγR is FcγRIIb, which directly antagonizes the signaling function of activating type I FcγRs on myeloid cells, or modulates the signaling of the B-cell receptor (BCR) on B cells. FcγRIIb comprises an immunoreceptor tyrosine inhibition motif (ITIM) at its intracellular region, which acts as the docking site for SHIP family phosphatases (Muta et al., 1994). Lastly, in contrast to the activating and inhibitory type I FcγRs, FcγRIIIb is processed as a GPI-anchored protein and hence lacks any intracellular signaling domains. However, previous studies have shown that FcγRIIIb could transduce activation signals through its association with other receptors, including FcγRIIa and complement receptors (Unkeless et al., 1995; Zhou and Brown, 1994).

With the exception of FcγRI, all type I FcγRs exhibit low affinity for IgG (KD for human IgG1= 10−5 – 10−7). Although type I FcγRs cannot mediate high affinity interactions with monomeric IgG, they can sufficiently engage multimeric IgG-antigen complexes (immune complexes) through high avidity interactions. Indeed, such low affinity multimeric interactions between type I FcγRs and IgG immune complexes represent the first step during receptor signaling, as IgG immune complexes induce receptor clustering and aggregation (Duchemin et al., 1994; Jouvin et al., 1994). In the case of activating type I FcγRs, receptor clustering triggers phosphorylation of their ITAM domains and the subsequent activation of several cytoplasmic kinases of the Src and Syk family kinases as well as the induction of pro-inflammatory signaling pathways (Duchemin et al., 1994; Odin et al., 1991; Swanson and Hoppe, 2004). Cellular activation induced upon FcγR crosslinking subsequently leads to pleiotropic biological responses, which vary greatly depending on the effector leukocyte type and include antibody-dependent cellular cytotoxicity (ADCC) or, phagocytosis (ADCP), release of cytokines and chemokines, leukocyte differentiation and survival, as well as modulation of T- and B-cell responses. In contrast to activating type I FcγRs, the inhibitory FcγRIIb recruits SHIP phosphatases following receptor clustering and phosphorylation of the ITIM domains (Ono et al., 1996; Ono et al., 1997). Recruited phosphatases promote the hydrolysis of phosphatidylinositol 3,4,5-triphosphate to phosphatidylinositol 4,5-biphosphate and inhibit the recruitment and activation of Src kinases and phospholipase C (PLC)γ, balancing thereby any pro-inflammatory signals initiated upon activating type I FcγR or BCR crosslinking (Ono et al., 1996; Ono et al., 1997; Pearse et al., 1999).

Type II FcγRs interact with the Fc domain of IgG at the CH2-CH3 interface in a 2:1 complex (receptor:IgG) and include DC-SIGN (or CD209) and CD23 (Pincetic et al., 2014; Sondermann et al., 2013). Both receptors belong to the C-type lectin receptor family and have a characteristic oligomeric structure that is stabilized by an α-helical coiled-coil stalk domain at the extracellular, ligand-binding region (Pincetic et al., 2014). Apart from the Fc domain of IgG, type II FcγRs have the capacity to engage other ligands. For example, DC-SIGN has been reported to interact with a number of carbohydrate ligands, especially high-mannose structures commonly found in heavily glycosylated glycoproteins, including the HIV-1 envelope protein, gp160 (Soilleux, 2003). Likewise, CD23 also mediates binding of the IgE Fc domain, a feature attributed to the intrinsic flexibility of the Cε3 domain of IgE (Borthakur et al., 2011; Dhaliwal et al., 2012). Given the diversity of the ligands with capacity to interact with type II FcγRs, the precise signaling cascades initiated upon receptor crosslinking are not well-defined and the downstream signaling events are expected to be highly dependent upon the nature of the ligand, the binding strength of the interaction, as well as the effector leukocyte types involved. Studies on the interaction of DC-SIGN – IgG Fc domain have shown that DC-SIGN engagement induces the expression and release of interleukin-33 (IL-33) by regulatory macrophages, which favors potent Th2 polarizing responses (Anthony et al., 2011; Anthony et al., 2008; Fiebiger et al., 2015). Indeed, IL-33 promotes the expansion and activation of Tregs to efficiently suppress Th1 and Th17 responses (Fiebiger et al., 2015), and induces the release of IL-4 from basophils that in turn upregulates the expression of the inhibitory FcγRIIb on effector macrophages to limit IgG-mediated inflammation (Anthony et al., 2011). On the other hand, CD23 engagement on B cells by the Fc domain of IgG regulates B cell selection and IgG affinity maturation by modulating the expression of B cell FcγRIIb in an autocrine manner (Wang et al., 2015).

Both type I and type II FcγRs exhibit a distinct pattern of cellular expression among the various leukocyte types, with different cell subsets typically co-expressing more than one FcγR type at any one time (Figure 1). Indeed, a key factor that influences the capacity of FcγR-mediated signaling to modulate immune processes is the FcγR expression levels and pattern among the various leukocyte populations. For example, with the exception of NK cells and B cells, most effector leukocytes co-express both activating and inhibitory type I FcγRs, and therefore the outcome of IgG-mediated cellular activation is largely determined by the opposing signaling activity of these FcγRs (Nimmerjahn and Ravetch, 2005). The expression of several FcγR genes fluctuates throughout leukocyte development and differentiation and can be regulated by cytokines and chemokines present at sites of inflammation, tissue injury and infection. For example, IFN-γ induces the expression of FcγRI on myeloid cells and FcγRIIIb on eosinophils, while it downregulates FcγRIIb expression (Boruchov et al., 2005; Dhodapkar et al., 2007; Uciechowski et al., 1998). In contrast, IL-4 induces the expression of CD23 in various leukocyte types, including T cells, monocytes, granulocytes, and macrophages, as well as it upregulates FcγRIIb expression on myeloid cells (Boruchov et al., 2005; Chan et al., 2010; te Velde et al., 1992; Yokota et al., 1988)(Figure 1). Alterations in the FcγR expression pattern readily influences the outcome of FcγR-mediated signaling and has profound consequences on the immunomodulatory functions initiated upon FcγR crosslinking by IgG immune complexes.

Figure 1. Overview of the expression pattern of type I and type II FcγRs in leukocyte populations.

Figure 1

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Both type I and type II FcγRs exhibit a distinct pattern of cellular expression among the various leukocyte types, with different cell subsets typically co-expressing more than one FcγR type at any one time. The expression of several FcγR genes fluctuates throughout leukocyte development and differentiation and can be regulated by cytokines and chemokines present at sites of inflammation, tissue injury and infection. Alterations in the FcγR expression pattern readily influences the outcome of FcγR-mediated signaling and has profound consequences on the immunomodulatory functions initiated upon FcγR crosslinking by IgG immune complexes.

IgG structure and function

IgG represents the major immunoglobulin class present in circulation (>75% over total serum immunoglobulin) and is produced during an immune response against foreign antigens. The characteristic Y shape of IgG is attributed to the different domains: the Fab domains (two domains per IgG molecule) and the Fc domain, which are linked by the hinge region. While the Fab domains mediate highly specific interactions with the antigen through their CDR regions, the Fc domain has the capacity to interact with a wide range of receptors and molecules, each with distinct functional properties. In addition to the type I and type II FcγRs discussed in the previous section, Fc domain-interacting proteins also include FcRn, which modulates IgG half-life and recycling (Ghetie and Ward, 2000), TRIM21, a cytosolic receptor with antiviral activity (Foss et al., 2015), as well as the complement component C1q (Lund et al., 1996). Previous mutational analyses and crystallographic studies have precisely mapped the interaction sites of these proteins with the Fc domain and determined which regions of the Fc domain structure confer recognition by FcγRs (Shields et al., 2001; Sondermann et al., 2000; Sondermann et al., 2001).

Since Fc domain recognition by FcγRs is predominantly mediated by protein-protein interactions, the primary amino acid backbone sequence of the IgG Fc domain represents the major determinant for Fc-FcγR interactions. Indeed, differences in the amino acid sequence among the various IgG subclasses (IgG1, IgG2, IgG3, and IgG4 in humans) and the Gm allotypes influence the capacity of the IgG Fc domain to interact with certain classes of FcγRs. For example, IgG1 and IgG3 have the highest affinity for type I FcγRs, exhibiting the highest cytotoxic activity in vivo, whereas, IgG2 and IgG4 interact poorly with all type I FcγRs. Given the differential affinity for FcγRs among the human subclasses, mAbs intended for clinical use are often designed based on the requirement to induce cytotoxic activity to mediate therapeutic effect. For example, therapeutic mAbs with cytotoxic activity against malignant cells are of the IgG1 subclass, whereas the IgG2 and IgG4 subclasses are often reserved for receptor-blocking or immunomodulatory antibodies to avoid cytotoxic elimination of target leukocytes.

In addition to the protein sequence of the Fc domain of IgG, differences in the amino acid sequence among the human FcγRs also influence Fc-FcγR interactions. For example, FcγRI represents the sole FcγR capable of mediating binding of monomeric IgG with high affinity; a property attributed to the presence of a third, extracellular Ig domain, which stabilizes Fc-FcγR interactions by acting as a spacer for the Fab domain (Kiyoshi et al., 2015). Likewise, single amino acid differences among the allelic variants of the low affinity type I FcγRs also modulate FcγR affinity for the IgG Fc domain. For example, the H131 allele of FcγRIIa represents the only FcγR variant capable of interacting with IgG2 (Bournazos et al., 2009). Likewise, the presence of a valine residue at position 158 of FcγRIIIa increases the receptor’s affinity for IgG1 and IgG3, which in turn augments the therapeutic activity of mAbs (Bibeau et al., 2009; Cartron et al., 2002; Musolino et al., 2008; Weng and Levy, 2003). Indeed, compared to carriers of the low affinity FcγRIIIa allele F158, genetic association studies have shown that the high affinity allele (V158) confers improved therapeutic response rate in trastuzumab-treated breast cancer patients, rituximab-treated lymphoma patients as well as in metastatic colorectal cancer patients treated with cetuximab (Bibeau et al., 2009; Cartron et al., 2002; Musolino et al., 2008; Weng and Levy, 2003).

Apart from the primary amino acid structure, the quaternary structure of the IgG represents a key determinant for interactions with the various types of FcγRs. A characteristic feature of the Fc domain is its horseshoe-like structure, which is accomplished by the unique organization of the two constant domains (CH2 and CH3) of the two heavy chains. The two CH3 domains are tightly associated at the C-terminus of IgG, whereas the two CH2 domains are spatially separated by the presence of an N-linked glycan structure conjugated to the amino acid backbone of CH2 domains at Asn297 (Anthony et al., 2012). The presence of this glycan structure within the hydrophobic cleft between the two CH2 domains maintains the Fc domain at a conformation permissive for FcγR binding. Loss of this glycan structure, either through mutation of the Asn297 residue, or enzymatic cleavage results in destabilization of the Fc domain structure and collapse of the CH2 domains, preventing thereby interactions with FcγRs (Albert et al., 2008).

In addition to maintaining the conformational structure of the CH2 domains to mediate Fc-FcγR interactions, the Fc-associated glycan structure also critically regulates the flexibility of the Fc domain, determining thereby its capacity to interact with type I and type II FcγRs (Sondermann et al., 2013). This is accomplished by specific modification of the structure and composition of the Fc-associated glycan. In particular, the core glycan structure is composed of a heptasaccharide moiety of mannose and N-acetylglucosamine residues, which can be modified through the addition of other saccharide units, including fucose, galactose, N-acetylglucosamine, and sialic acid (Anthony et al., 2012). Previous analyses of the Fc glycan composition of IgG purified from human serum revealed substantial heterogeneity, which readily influence the IgG affinity for type I and type II FcγRs (Wang et al., 2015). For example, glycan structures lacking the branching fucose residue exhibit increased affinity for FcγRIIIa through stabilized glycan-glycan interactions between the Fc domain and FcγRIIIa (Ferrara et al., 2011). The increased FcγRIIIa affinity of afucosylated IgG glycovariants confers improved cytotoxic activity over their fucosylated counterparts and the concept of Fc glycoengineering has been successfully applied for the development of therapeutic mAbs with enhanced Fc effector function (Liu et al., 2015; Shields et al., 2002). Likewise, the presence of terminal sialic acids at the Fc-associated glycan increases the flexibility of the Fc domain, by destabilizing its quaternary structure (Sondermann et al., 2013). Consequently, sialylated Fc glycoforms have the capacity to interact with the type II FcγRs, DC-SIGN and CD23 and mediate downstream immunomodulatory functions (Anthony et al., 2011; Anthony et al., 2008; Wang et al., 2015).

Although the presence of the Fc-associated glycan structure is required for Fc-FcγR interactions, the affinity of the Fc domain for type I and type II FcγRs is finely tuned by the composition of the glycan structure. Given the critical role of the Fc-associated glycan in determining the Fc domain affinity for type I and type II FcγRs, Fc glycan modifications are subject to active regulatory mechanisms that dynamically control the composition of the glycan structure, influencing thereby Fc effector functions. Analysis of the Fc glycan structure has shown that the glycan composition is dynamically regulated in chronic inflammatory conditions, in response to systemic metabolic changes, upon vaccination, and during infection (de Man et al., 2014; Espy et al., 2011; Theodoratou et al., 2016; van de Geijn et al., 2009; Wang et al., 2015). For example, inflammatory diseases, like rheumatoid arthritis (RA) and Wegener’s granulomatosis are characterized by reduced galactosylation and sialylation, whereas disease severity during secondary Dengue infection is associated with increased levels of afucosylation, which confers enhanced binding to FcγRIIIa (de Man et al., 2014; Espy et al., 2011; Wang et al., 2017). Likewise, major deviations at the baseline Fc glycan profile have been reported during pregnancy as well as in certain neoplastic diseases (de Man et al., 2014; Theodoratou et al., 2016; van de Geijn et al., 2009). Analysis of the Fc glycan composition of antigen-specific IgG elicited upon influenza hemagglutinin (HA) vaccination in humans revealed that specific Fc glycoforms are enriched at different stages following vaccination (Wang et al., 2015). For example, the levels of sialylated and fucosylated glycoforms of HA-specific IgGs are significantly increased following vaccination, reaching a peak on day 7 post-vaccination (Wang et al., 2015). Then, by week 3, both sialylated and fucosylated Fc glycoforms exhibit a significant drop in their serum levels, before returning to baseline a few weeks later (weeks 5–7 post-vaccination). These changes in the glycan composition are accomplished by the specific modulation in the expression of the enzymes that catalyze the addition of saccharide moieties to the core glycan structure. These enzymes include galactosyl-, fucosyl- and sialyltransferases, which mediate the transfer of galactose, fucose and sialic acids residues, respectively. Quantification of the expression of the sialyltransferase St6Gal1 and of the fucosyltranserase, Fut8, in plasmablasts and memory B cells at different time points following influenza vaccination identified distinct changes in their expression pattern over time, coinciding with the observed fluctuation at the levels of certain Fc glycoforms of HA-specific IgGs (Wang et al., 2015).

Comparable findings have been also observed in mechanistic studies using mouse models of immune complex-mediated nephrotoxic nephritis and collagen-induced arthritis (CIA) (Kaneko et al., 2006; Ohmi et al., 2016). In both models, immunization induced a significant reduction of Fc sialylation of antigen-specific IgGs, supporting the presence of regulatory mechanisms that modulate Fc glycosylation in response to antigenic stimulation (Kaneko et al., 2006; Ohmi et al., 2016). Asialylated IgGs were the major driver of IgG-mediated inflammation and were necessary for disease development. Likewise, conditional genetic deletion of St6Gal1 in B cells (AID-Cre, St6Gal1fl/fl) diminished sialylation of anti-collagen II IgGs elicited upon immunization and the resulting asialylated IgGs exacerbated joint inflammation in the CIA model (Ohmi et al., 2016). In contrast, sialylation of arthritogenic IgGs eliminated their pathogenic activity in mouse models of arthritis (Ohmi et al., 2016). These findings provide mechanistic evidence to support a key role for Fc glycan modulation during antibody responses and disease development and have been previously confirmed by clinical studies in human RA patient cohorts, which exhibit reduced levels of sialylated IgGs that correlate with disease severity (de Man et al., 2014; Ohmi et al., 2016).

Biological consequences of Fc-FcγR interactions during immune responses

Engagement of type I and type II FcγRs by the Fc domain of IgG has the capacity to initiate pleiotropic immunomodulatory functions with diverse biological consequences that can impact several aspects of innate and adaptive immunity (Bournazos and Ravetch, 2015)(Table 1). Although the classical definition of Fc effector function has previously been the induction of antibody-dependent cellular cytotoxicity and phagocytosis, substantial evidence highlights that Fc effector functions actually represent a spectrum of diverse activities that span all aspects of innate and adaptive immunity. Indeed, Fc-FcγR interactions promote innate immune cell activation that lead to effector activities and the expression of pro-inflammatory and immunomodulatory mediators with profound impact on cellular differentiation and survival. Additionally, FcγR-mediated pathways influence macrophage polarization, enhance the functional activity of antigen-presenting cells, including their capacity for antigen processing and presentation, as well as regulate the maturation and activation of dendritic cells (Bournazos et al., 2015). Lastly, since B cells express both the type I FcγR, FcγRIIb and the type II FcγR, CD23 at most stages throughout their differentiation, IgG responses are largely regulated by Fc-FcγR interactions (Wang et al., 2015). Indeed, FcγR-mediated pathways control B cell activation and selection, IgG affinity maturation, as well as IgG production and plasma cell survival. Given the significant contribution of the FcγR-mediated immunomodulatory activities in the regulation of T- and B-cell responses, manipulation of FcγR function could lead to the design of novel vaccination strategies with robust and sustained cellular and humoral immune responses.

Table 1.

Immunomodulatory Activity of FcγR pathways

Cell type FcγR Cellular Effects Biological Effects
T cell Immunity Dendritic cells FcγRIIa Cell maturation, upregulation of co-stimulatory molecules Enhanced antigen processing and presentation
Induction of T cell responses
FcγRIIb Inhibit FcγRIIa effects Limit dendritic cell maturation
IgG Immunity B cells CD23 FcγRIIb upregulation Increased threshold for B cell selection
FcγRIIb Oppose BCR signaling
Apoptosis induction		 Eliminate low affinity BCR B cells
Plasma cells FcγRIIb Apoptosis induction Regulation of plasma cell apoptosis
Control of IgG production
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T cell-mediated Immunity

FcγRs have been originally described as phagocytic receptors and indeed, a major function of FcγRs is the highly efficient uptake of IgG-opsonized targets, which can range from small proteins, like toxins to virions, bacteria or even whole cells. Although phagocytosis is a common function to most FcγRs, the exact phagocytic capacity of FcγR-bearing effector leukocytes for IgG-coated targets is largely dependent upon the leukocyte type, differentiation stage as well as the levels of FcγR expression. Initial steps following receptor oligomerization and phosphorylation include actin remodeling and cytoskeletal reorganization, leading ultimately to the endocytosis of the FcγR-IgG complex (Bergtold et al., 2005; Bonnerot et al., 1998; Dale et al., 2008; Hoffmann et al., 2012; Odin et al., 1991; Regnault et al., 1999). Both activating and inhibitory type I FcγRs can mediate phagocytosis; however, crosslinking of activating FcγRs is also accompanied by the induction of potent pro-inflammatory pathways that promote enhanced endosomal maturation and efficient lysosomal fusion (Amigorena et al., 1992). In turn, these effects greatly augment antigen processing and presentation to MHC class II molecules (Amigorena et al., 1992; Regnault et al., 1999). In addition to enhanced antigen uptake and presentation, immune complex endocytosis through activating type I FcγRs is also accompanied by cellular activation and the induction of pro-inflammatory chemokine and cytokine expression, which in turn influence the differentiation, effector activities and survival of antigen presenting cells (Hoffmann et al., 2012; Regnault et al., 1999).

A number of studies on the role of FcγRs in dendritic cell function revealed that dendritic cell maturation and activity is regulated by the opposing signaling function of activating and inhibitory type I FcγRs (Figure 2). Under steady-state conditions, dendritic cells express both the inhibitory FcγRIIb and the activating FcγRIIa and the balanced activity of these receptors prevents inappropriate or uncontrolled dendritic cell maturation upon encountering IgG immune complexes. Since the balance of activating and inhibitory FcγR signaling determines the threshold for immune complex-mediated dendritic cell maturation, FcγR expression levels are tightly regulated and can be modulated by certain mediators present in the inflammatory milieu. Examples include IL-4 that upregulates FcγRIIb expression and IFN-γ that stimulates FcγRI expression (Boruchov et al., 2005; Dhodapkar et al., 2005; Uciechowski et al., 1998). Additionally, co-engagement and signaling through other activating receptors, like PAMPs act synergistically with activating FcγR signaling, skewing the threshold for immune complex-mediated maturation of dendritic cells (Boruchov et al., 2005; Clynes et al., 1999; Desai et al., 2007; Dhodapkar et al., 2007; Dhodapkar et al., 2005). Indeed, under physiological conditions, stimulation of dendritic cells with IgG immune complexes is insufficient for cellular maturation, as FcγRIIb-mediated signaling overrides any signals from activating FcγRs (Boruchov et al., 2005; Dhodapkar et al., 2007). However, when activating FcγR signaling is coupled with TLR stimulation, robust dendritic cell maturation is induced. Early studies using mouse strains encompassing genetic deletions either of the inhibitory FcγRIIb or the FcR γ chain, which is required for activating FcγR expression highlighted the key role of these receptors in modulating dendritic cell function and the subsequent induction of T cell-mediated immunity. For example, FcγRIIb genetic deletion or mAb-mediated blocking of FcγRIIb on dendritic cells resulted in robust cellular maturation and upregulation of co-stimulatory and MHC class II molecules following stimulation with IgG immune complexes (Boruchov et al., 2005; Clynes et al., 2000; Dhodapkar et al., 2007; Dhodapkar et al., 2005).

Figure 2. The role of FcγR-mediated signaling in the regulation of dendritic cell function and T cell responses.

Figure 2

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Human dendritic cells (DCs) express two classes of type I FcγRs: FcγRIIa and FcγRIIb with activating or inhibitory signaling activities, respectively. The opposing signaling activities of these FcγRs is a key homeostatic mechanism that regulates DC function and T-cell activation. Engagement of FcγRIIb by IgG immune complexes fails to induce DC maturation, as pro-inflammatory signals from FcγRIIa are counterbalanced by FcγRIIb. In contrast, preferential engagement of FcγRIIa stimulates DC activation, leading to enhanced antigen presentation, the release of pro-inflammatory chemokines and cytokines, and T-cell activation and expansion.

More recently, studies on the role of FcγR in dendritic cell function using conditional knock-out and FcγR humanized mouse strains provided additional insights into the mechanisms of FcγR-mediated modulation of antigen processing and T cell immunity, with clear implications for vaccine design (DiLillo and Ravetch, 2015). The rationale for these studies came from the clinical observation that a fraction of non-Hodgkin lymphoma patients treated with anti-CD20 mAbs, like rituximab, exhibits evidence for a vaccinal, memory T cell response (Abes et al., 2010; Hilchey et al., 2009). In particular, relapsed patients who are re-treated with the same mAb demonstrate enhanced and rapid therapeutic responses compared to their initial response; an effect that has been attributed to the induction of robust anti-tumor CD8 responses. Similar evidence for vaccinal T cell responses has been described for patients with HER2+ and MUC1+ tumors following mAb treatment (de Bono et al., 2004; Taylor et al., 2007). To investigate the underlying mechanisms for this clinical phenomenon, the role of FcγR-mediated signaling in dendritic cells has been evaluated using FcγR-humanized mice in a model of human CD20+ lymphoma (DiLillo and Ravetch, 2015). These studies revealed an absolute requirement for dendritic cell FcγRIIa expression in the generation of anti-tumor T cell responses, as Fc engineered variants of anti-CD20 mAbs with enhanced affinity for FcγRIIa demonstrated augmented IgG-mediated T cell responses; an effect attributed to the increased threshold for FcγRIIb-mediated inhibition.

These studies demonstrated that the therapeutic activity of anti-CD20 mAbs is the outcome of two distinct FcγR-mediated pathways: (i) initial cytotoxic elimination of CD20+ lymphoma cells accomplished by FcγRIIIa on macrophages and monocytes, (ii) induction of T cell responses through FcγRIIa engagement on dendritic cells by anti-CD20 immune complexes (DiLillo and Ravetch, 2015). Previous attempts to modulate the activity of antitumor mAbs were focused on enhancing their capacity to interact with FcγRIIIa to augment their cytotoxic activity. For example, obinutuzumab, a second generation anti-CD20 mAb optimized for enhanced binding to FcγRIIIa through engineering of the Fc-associated N-linked glycan structure exhibited improved therapeutic activity in chronic lymphocytic leukemia patients compared to the first generation, non-Fc engineered anti-CD20 mAb, rituximab (Goede et al., 2014). Similarly, several therapeutic mAbs in preclinical development are optimized for increased FcγRIIIa binding and exhibit enhanced cytotoxic activity (Gerdes et al., 2013; Horton et al., 2008; Shields et al., 2002). However, based on the recent studies on the specific FcγR requirements for therapeutic mAbs to achieve potent antitumor effect, the design of mAb-based therapeutics should focus on enhancing their capacity to engage both FcγRIIIa and FcγRIIa to induce cytotoxicity and T cell memory responses, respectively (DiLillo and Ravetch, 2015). This approach would maximize the therapeutic potential of antibodies, providing not only immediate therapeutic benefit, but also sustained and long-term protection.

IgG-mediated Immunity

With the exception of NK cells, activating type I FcγR expression is always coupled with the expression of the inhibitory FcγRIIb in effector leukocytes. Indeed, the major role of FcγRIIb is to limit activating FcγR signaling, acting as a key homeostatic mechanism to prevent uncontrolled or inappropriate IgG-mediated inflammation. However, B cells express only the inhibitory FcγRIIb throughout development and differentiation, without co-expressing any activating type I FcγR. In the absence of activating FcγR expression, the main role of B cell FcγRIIb is to regulate the activity of the BCR, controlling thereby several aspects of B cell responses, including B cell selection and activation, as well as IgG affinity maturation. For example, in the presence of unopposed FcγRIIb crosslinking and signaling, B cells undergo apoptosis, eliminating thereby B cells with low or no affinity for the BCR (Ono et al., 1996; Ono et al., 1997; Pearse et al., 1999). However, co-engagement of the BCR with FcγRIIb attenuates any pro-apoptotic signals, leading to B cell survival. Given the role of FcγRIIb during B cell selection, FcγRIIb expression levels and signaling activity on B cells represent key determinants for the threshold of BCR-mediated cellular activation and survival. Indeed, fluctuations in the FcγRIIb expression or signaling activity stemming from genetic variants of FCGR2B constitute risk factors for susceptibility to autoimmune pathologies, including systemic lupus erythematosus (Blank et al., 2005; Floto et al., 2005; Mueller et al., 2013; Su et al., 2004). Likewise, mouse studies using Fcgr2b-deficient strains revealed that FcγRIIb signaling is essential for regulating the threshold of B cell activation, controlling antibody responses, and maintaining peripheral tolerance. Immunization of FcγRIIb−/− mice fails to induce potent antibody responses, and the elicited IgGs are characterized by high titer and low affinity, indicative of insufficient B cell selection (Bolland and Ravetch, 2000; Bolland et al., 2002). FcγRIIb also plays a key regulatory role even when BCR expression is diminished, as in the case of plasma cells. Crosslinking of plasma cell FcγRIIb transduces pro-apoptotic signals, controlling plasma cell survival and in turn IgG production (Ono et al., 1996; Xiang et al., 2007). This negative feedback loop represents a homeostatic mechanism, by which immune complexes generated during an immune response signal through FcγRIIb to induce plasma cell apoptosis, preventing thereby uncontrolled IgG production.

In addition to FcγRIIb, B cells also express the type II FcγR, CD23. Although initially described as the low affinity receptor for IgE with the main function to regulate IgE production by B cells, CD23 has been recently described to exhibit ligand binding activity for sialylated IgG (Sondermann et al., 2013; Wang et al., 2015). Indeed, this activity represents an additional determinant for regulating B cell activation and selection through modulation of FcγRIIb expression on B cells. In particular, engagement of CD23 on B cells by sialylated IgG immune complexes induces the upregulation of FcγRIIb, which subsequently raises the threshold for B cell selection (Wang et al., 2015). Given the key role of the sialylated IgG-CD23-FcγRIIb pathway during IgG responses, novel vaccination strategies could be suggested based on the specific modulation of this pathway to elicit high affinity IgG responses. Indeed, in a recent study that utilized a model of influenza hemagglutinin (HA) vaccination, administration of sialylated Fc anti-HA immune complexes induced the generation of higher affinity anti-HA IgG responses, with broadly protective activity (Wang et al., 2015). In contrast, genetic deletion of Cd23 or immunization with asialylated Fc anti-HA immune complexes had little impact on IgG responses, and failed to elicit high affinity IgGs. Based on these findings, specific modulation of the activity of this pathway could provide a promising strategy for eliciting potent IgG responses, with high affinity and broad protective activity, especially for challenging antigens exhibiting poor immunogenicity.

Concluding remarks

FcγR-mediated pathways contribute significantly to the therapeutic activity of several mAbs and Fc effector function represents a key component of their activity (Bournazos and Ravetch, 2015). To improve the Fc effector function of therapeutic mAbs, a previously employed strategy involved Fc domain engineering for enhanced binding to FcγRIIIa, the main FcγR type that drives ADCC activity by macrophages and NK cells (Goede et al., 2014; Horton et al., 2008). Clinical evaluation of Fc-optimized mAbs revealed a significant improvement in their therapeutic activity, consistent with their enhanced capacity to induce cytotoxicity of IgG-opsonized targets (Goede et al., 2014).

However, Fc effector functions are not limited to IgG-mediated cytotoxicity, but as several studies have clearly shown, Fc-FcγR interactions readily influence the outcome of IgG-mediated inflammation and immunity. Better understanding of the precise role and function of FcγR-mediated pathways during the induction of adaptive immune responses is necessary for the development of antibody-based therapeutics that would exhibit with not only short-term therapeutic benefit, but will also induce broadly protective, long-lasting immunity. Preliminary studies in animal models demonstrated that specific activation of distinct FcγR-mediated pathways significantly improves the the protective activity of therapeutic antibodies, suggesting novel strategies to harness the immunomodulatory function of FcγRs to elicit sustained and robust immune responses (DiLillo and Ravetch, 2015; Wang et al., 2015)(Table 1). We anticipate that the in-depth study of the Fc effector functions of IgG antibodies will lead to the development of the next generation of mAb therapeutics that will be optimized not only for improved therapeutic activity, but also for augmented capacity to elicit host immune responses for long-term protection. These Fc-optimized mAbs will unleash the full potential of Fc effector activities, offering significant therapeutic benefits.

Acknowledgments

We acknowledge support from the Rockefeller University. Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (P01AI100148, U19AI111825, U19AI109946), the National Cancer Institute (R35CA196620, P01CA190174), and the Bill & Melinda Gates Foundation (OPP1124068). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SB is an amfAR Mathilde Krim Fellow in Basic Biomedical Research (109519-60-RKVA). The authors have no conflicting financial interests.

Footnotes

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