Leukocytes express Fc receptors that bind to the constant regions of antibodies, and thereby promote the phagocytosis of Ig-coated particles and deliver signals that regulate the activities of the leukocytes; other Fc receptors are involved in the functions of natural killer (NK) cells and mast cells. Fc receptors for different Ig heavy-chain classes are expressed on many leukocyte populations and serve diverse functions in immunity. They may be classified into two broad groups based on their functions: the signaling FcRs, which are involved in phagocytosis and activation or inhibition of various cells, and the trafficking FcRs, which transport antibodies across membranes but do not signal and are not involved in phagocytosis (Table 1). Of these Fc receptors, the ones that are most important for phagocytosis of opsonized particles are receptors for the heavy chains of IgG antibodies, called Fcγ receptors, and these are the receptors that will be primarily considered in this chapter. In Chapter 20, we will discuss the Fc receptors that bind IgE. In Chapter 5, we described the neonatal Fc receptor (FcRn), which is expressed in the placenta, and on vascular endothelium and other cell types and has unique functions related to IgG transport across the placenta and the protection of antibodies of this isotype from turnover. In Chapter 14, we will discuss the placental function of FcRn and the role of the poly-Ig receptor in the transport of mainly IgA across mucosal epithelia.
Table1. Fc Receptors
Fcγ receptors have been classified into three groups, based on their affinities for heavy chains of different IgG subclasses; two of these groups have multiple isoforms. Different Fc receptors are also expressed on different cell types (see Table1). In general, IgG1- and IgG3-containing immune complexes bind efficiently to activating Fc receptors and IgG2-containing complexes do not bind well. IgG4 has a very low affinity for activating Fc receptors, and the biological function of this antibody isotype is unclear. All Fc receptors are optimally activated by antibodies bound to their antigens and not by free circulating antibodies. The engagement of most Fc receptors results in cellular activation, except for FcγRIIB, which is an inhibitory receptor; the receptors closely related structurally to FcγRIIB, namely FcγRIIA and FcγRIIC, are activating receptors.
All Fcγ receptors contain a ligand-binding chain, called the α chain, that recognizes IgG heavy chains (Fig. 1). Differences in specificities or affinities of each FcγR for the various IgG subclasses are based on differences in the structure of these α chains. In all the FcRs, except FcγRII (A, B and C), the α chain is associated with one or more additional polypeptide chains involved in signal transduction (see Fig. 1). Signaling functions of all forms of FcγRII are mediated by the activating or inhibitory motifs in the cytoplasmic tail of this single-chain receptor.
Fig1. Subunit composition of Fcγ receptors. Schematic models of the different human Fc receptors illustrate the Fc-binding α chains and the signaling subunits. FcγRIIIB is a glycophosphatidylinositol-anchored membrane protein with no known signaling functions. FcγRIIA and IIC are structurally similar low-affinity activating receptors with slightly different patterns of expression. Note that although FcγRIIA/C and FcγRIIB are both designated CD32, they are different proteins with distinct functions (see text). The neonatal FcR (FcRn) resembles class I major histocompatibility complex molecules structurally but does not have a peptide-binding cleft. Ig, Immunoglobulin; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif.
The three major groups of IgG-specific Fc receptors are described below.
• FcγRI (CD64) is the major phagocyte Fcγ receptor. It is expressed on macrophages and neutrophils and binds IgG1 and IgG3 with high affinity (dissociation constant [Kd ] of 10−8 to 10−9 M). (In mice, FcγRI preferentially binds IgG2a and IgG2b/2c antibodies.) The large extracellular amino terminal region of the Fc-binding α chain folds into three tandem Ig-like domains. The α chain of FcγRI is associated with a disulfide-linked homodimer of a signaling protein called the FcR γ chain. This γ chain is also found in the signaling complexes associated with FcγRIII, FcαR, and FcεRI. The γ chain has only a short extracellular amino terminus but a large cytoplasmic carboxyl terminus, which is structurally homologous to the ζ chain of the T-cell receptor (TCR) complex. Like the TCR ζ chain, the FcR γ chain contains an immunoreceptor tyrosine-based activation motif (ITAM) that couples receptor clustering to activation of protein tyrosine kinases. Cross-linking of several Fc receptor–bound IgG molecules by multivalent antigens results in cell activation.
• FcγRII (CD32) in humans binds IgG1 and IgG3 with a low affinity (Kd 10−6 M). Gene duplication and diversification have resulted in the generation of three forms of this receptor, called FcγRII A, B, and C. These isoforms have similar extra cellular domains and ligand specificities but differ in cytoplasmic tail structure, cell distribution, and functions. FcγRIIA is expressed by neutrophils, mononuclear phagocytes, and dendritic cells (DCs) and participates in the phagocytosis of opsonized particles, while FcγRIIC is expressed in mononuclear phagocytes, neutrophils, and NK cells. The cytoplasmic tails of FcγRIIA and FcγRIIC contain ITAMs and, on clustering by IgG1- or IgG3-coated particles or cells, can deliver an activation signal to phagocytes. On DCs, this receptor can contribute to capture of antigen in immune complexes and presentation of processed protein antigens to T cells. FcγRIIB is an inhibitory receptor expressed on myeloid cells and B cells and is the only Fc receptor on B cells. Its role in antibody feedback.
• FcγRIII (CD16) is also a low-affinity receptor for IgG. The extra cellular ligand-binding portion of FcγRIII is similar to FcγRII in structure, affinity, and specificity for IgG. This receptor exists in two forms, encoded by separate genes. The FcγRIIIA isoform is a transmembrane protein expressed mainly on NK cells, but also expressed on macrophages and DCs. FcγRIIIA associates with homodimers of the FcR γ chain, homodimers of the TCR ζ chain, or heterodimers composed of an FcR γ chain and a ζ chain. These associated chains contain ITAMs that deliver activating signals on antibody binding to the Fc receptors and are thus necessary for the functions of the receptors. The FcγRIIIB isoform is a GPI-linked protein expressed on neutrophils; it does not mediate phagocytosis or trigger neutrophil activation, and its function is poorly understood.
• Other Fc receptors. FcεRI is a receptor for IgE expressed mainly on mast cells and basophils. The FcαR receptor (CD89) expressed on monocytes, macro phages, neutrophils, and eosinophils associates with homodimers of the FcR γ chain and is an activating receptor that can bind to both IgM and IgA and aids in phagocytosis of IgA coated microbes.
• Cytosolic FcR (TRIM21). An unusual high affinity Fc receptor for all subclasses of IgG is found in the cytosol of nucleated cells. Although neutralizing antibodies block viral entry into cells, nonneutralizing antibodies do not. When a virus particle bound to a nonneutralizing IgG antibody is internalized and transported into the cytosol, the IgG component is rec ognized with high affinity by TRIM21 (TRIpartite Motif containing 21). TRIM21 can also bind to the Fc regions of IgM and IgA and, while the affinity for those subclasses is low, IgM and IgA antibodies bound to viruses that have been internalized may also use this mechanism for viral elimination. The intrinsic ubiquitin E3 ligase activity of TRIM21 is triggered when it binds to IgG, and it marks the viral particle–IgG com plex for ubiquitination and proteasomal degradation.
Role of Fcγ Receptors in Phagocytosis and Activation of Phagocytes
Binding of Fc receptors on phagocytes to particles (e.g., microbes) coated with multiple antibody molecules leads to engulfment of the particles and activation of the phagocytes to destroy the ingested microbes (Fig.2). The IgG subclasses that bind best to these receptors (IgG1 and IgG3) are the most efficient opsonins for promoting phagocytosis. As discussed earlier, FcγRI is the high-affinity Fcγ receptor on phagocytic cells, and it is the most important receptor for phagocytosis of opsonized particles.
Fig2. Antibody-mediated opsonization and phagocytosis of microbes. Antibodies of certain immunoglobulin G (IgG) subclasses bind to microbes and are then recognized by Fc receptors on phagocytes. Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes.
Opsonized particles are internalized into vesicles known as phagosomes, which fuse with lysosomes, and the phagocytosed particles are destroyed in these phagolysosomes. Activation of the phagocyte is necessary for both internalization and destruction of microbes. Activation requires cross-linking of the FcRs by several adjacent Ig molecules (e.g., on antibody coated microbes or in immune complexes). Cross-linking of the ligand-binding α chains of an FcR results in signal trans duction events that are similar to those that occur after antigen receptor cross-linking in lymphocytes. These include SRC kinase–mediated tyrosine phosphorylation of the ITAMs in the signaling chains of the FcRs; SH2 domain–mediated recruitment of SYK family kinases to the ITAMs; activation of phosphatidylinositol 3-kinase; recruitment of adaptor molecules, including SLP76 and BLNK; and recruitment of enzymes, such as phospholipase Cγ and TEC family kinases. These events lead to generation of inositol trisphosphate and diacylglycerol and sustained increase in cytosolic calcium.
The signaling pathways downstream of Fcγ receptors induce a number of responses in leukocytes, including transcription of genes encoding cytokines, inflammatory mediators, and microbicidal enzymes, and mobilization of the cytoskeleton leading to phagocytosis, granule exocytosis, and cell migration. The major microbicidal substances produced in the activated phagocytes are reactive oxy gen species, nitric oxide, and hydrolytic enzymes. These are the same substances produced by phagocytes activated in innate immune responses. The microbicidal substances may damage tissues; this mechanism of antibody-mediated tissue injury is important in hypersensitivity diseases. Knockout mice lacking the ligand-binding α chain of FcγRI or the signal transducing FcR γ chain are defective in antibody-mediated defense against microbes and do not develop some forms of IgG antibody-mediated tissue injury, thus demonstrating the essential role of Fc receptors in these processes.
Inhibitory Signaling by the FcγRIIB Receptor
The FcγRIIB receptor is an inhibitory Fc receptor that was described earlier in the context of inhibitory signaling in B cells and the phenomenon of antibody feedback. FcγRIIB is also expressed on DCs, neutrophils, macrophages, and mast cells and may play a role in regulating the responses of these cells to activating Fc receptors and other stimuli. A somewhat empirical but often useful treatment of several auto immune diseases is the intravenous administration of pooled human IgG, called intravenous immunoglobulin (IVIG). IVIG may both increase the expression of FcγRIIB and bind to this receptor and deliver inhibitory signals to B lymphocytes and myeloid cells, thus reducing antibody production and dampening inflammation. However, the mechanisms by which IVIG reduces inflammation in disease remain poorly understood.
