Info

FcR

Affinity for Immunoglobulin

Cell Distribution

Function

Fcy RI (CD64)

High (Kd < 10-9 M); binds IgG1 and IgG3, can bind monomeric IgG

Macrophages, neutrophils; also eosinophils

Phagocytosis; activation of phagocytes

Fcy RIIA (CD32)

Low (Kd > 10-7 M)

Macrophages, neutrophils; eosinophils, platelets

Phagocytosis; cell activation (inefficient)

Fcy RIIB (CD32)

Low (Kd > 10-7 M)

B lymphocytes

Feedback inhibition of B cells

FCy RIIC (CD32)

Low (Kd > 10-7 M)

Macrophages, neutrophils, NK cells

Phagocytosis, cell activation

Fcy RIIIA (CD16)

Low (Kd > 10-6 M)

NK cells

Antibody-dependent cell-mediated cytotoxicity

FCy RIIIB (CD16)

Low (Kd > 10-6 M); GPI-linked protein

Neutrophils

Phagocytosis (inefficient)

FceRI

High (Kd > 10-10 M); binds monomeric IgE

Mast cells, basophils, eosinophils

Cell activation (degranulation)

FceRII (CD23)

Low (Kd > 10-7 M)

B lymphocytes, eosinophils, Langerhans cells

Unknown

FcaR (CD89)

Low (Kd > 10-6 M)

Neutrophils, eosinophils, monocytes

Cell activation?

GPI, glycophosphatidylinositol; NK, natural killer.

only a short extracellular amino terminus but a large cytoplasmic carboxyl terminus, which is structurally homologous to the Z chain of the T cell receptor (TCR) complex. Like the TCR Z chain, the FcR y chain contains an immunoreceptor tyrosine-based activation motif (ITAM) that couples receptor clustering to activation of protein tyrosine kinases. FcyRI, like the high-affinity receptor for IgE (see Chapter 19), is constantly saturated with its IgG ligands. Triggering of Fc receptors requires that receptors be clustered in the plane of the membrane, and clustering and consequent receptor activation of FcyRI is mediated by multivalent antigen crosslinking receptor-bound IgG molecules.

Transcription of the FcyRI gene and expression of FcyRI on macrophages is stimulated by interferon-y (IFN-y). The antibody isotypes that bind best to Fcy receptors (such as IgG2a/2c in mice) are also produced in part as a result of IFN-y-mediated isotype switching of B cells. In addition, IFN-y directly stimulates the microbicidal activities of phagocytes (see Chapter 10).

• FcyRII (CD32) binds human IgG subtypes (IgG1 and IgG3) with a low affinity (Kd 10-6 M). In humans, gene duplication and diversification has resulted in the generation of three forms, called FcyRII A, B, and C. These isoforms have similar extracellular domains and ligand specificities but differ in cytoplasmic tail structure, cell distribution, and functions. FcyRIIA is expressed by neutrophils and mononuclear phagocytes and participates in the phagocytosis of opsonized particles, while FcyRIIC is expressed in mononuclear phagocytes, neutrophils, and NK cells. The cytoplasmic tails of FcyRIIA and FcyRIIC contain ITAMs and, on clustering by IgG1- or IgG3-coated particles or cells, can deliver an activation signal to phagocytes. FcyRIIB is an inhibitory receptor expressed on all immune cells other than NK cells and is the only Fc receptor on B cells. Its function is described later.

• FcyRin (CD16) is also a low-affinity receptor for IgG. The extracellular ligand-binding portion of FcyRIII is similar to FcyRII in structure, affinity, and specificity for IgG. This receptor exists in two forms, each encoded by a separate gene. The FcyRIIIA isoform is a transmembrane protein expressed mainly on NK cells. FcyRIIIA associates with homodimers of the FcR y chain, homodi-mers of the TCR Z chain, or heterodimers composed of the FcR y chain and the Z chain. This association is necessary for the cell surface expression and function of these FcRs because intracellular activating signals are delivered through the ITAMs in these signaling chains. The FcyRIIIB isoform is a glycophosphatidylino-sitol (GPI)-linked protein expressed on neutrophils; it does not mediate phagocytosis or trigger neutrophil activation, and its function is poorly understood.

Most of the FcRs serve to activate the cells on which they are expressed. FceRI is described in Chapter 19, in the context of mast cell activation. The function of FcaR is not well established.

Role of Fcy Receptors in Phagocytosis and Activation of Phagocytes

Phagocytosis of IgG-coated particles is mediated by binding of the Fc portions of opsonizing antibodies to Fcy receptors on phagocytes. Therefore, the IgG subtypes that bind best to these receptors (IgG1 and IgG3) are the most efficient opsonins for promoting phagocytosis. As discussed before, FcyRI (CD64) is high-affinity Fcy receptor on phagocytic cells, and it is the most important receptor for phagocytosis of opsonized particles.

Binding of Fc receptors on phagocytes to multivalent antibody-coated particles leads to engulfment of the particles and the activation of phagocytes (Fig. 12-4). The particles are internalized into vesicles known as phago-somes, which fuse with lysosomes, and the phagocytosed particles are destroyed in these phagolysosomes.

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