Type I and type II Fc receptors regulate innate and adaptive immunity

Abstract

Antibodies produced in response to a foreign antigen are characterized by polyclonality, not only in the diverse epitopes to which their variable domains bind but also in the various effector molecules to which their constant regions (Fc domains) engage. Thus, the antibody's Fc domain mediates diverse effector activities by engaging two distinct classes of Fc receptors (type I and type II) on the basis of the two dominant conformational states that the Fc domain may adopt. These conformational states are regulated by the differences among antibody subclasses in their amino acid sequence and by the complex, biantennary Fc-associated N-linked glycan. Here we discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders.

Figure 1.. Reciprocal engagement of Type-I and Type-II receptors by IgG Fc domain.

a) The Fc domain alternates between open and closed conformations depending on the sialylation status of the Fc glycan. Non-sialylated Fc adopts an open conformation capable of binding Type-I receptors near the hinge-proximal surface, whereas the binding site for Type-II receptors remains inaccessible. Upon sialic acid conjugation, the Fc acquires a closed conformation that occludes the Type-I receptor binding site and reveals a binding site for Type-II receptors. (PDB file:3AVE, for non-sialylated Fc structure). b) Schematic and expression profile of the human Type-I and Type-II receptors known to bind the Fc domain of IgG. Type-I and Type-II receptors form part of the Ig-family and C-type lectin receptors, respectively. Mac, macrophage; PMN, polymorphonuclear leukocytes; NK, natural killer; FDC, follicular dendritic cell; DC, dendritic cell.

Figure 2.. Glycan-dependent modulation of Fc structure.

a) Crystal structure of Fc fragment of human IgG1 (PDB 1H3Y) depicting the orientation of the glycan arms with respect to the CH2 domains of the two heavy chains. The interaction between the α1,3-arms maintains the Fc in the appropriate conformation for FcγR binding. b) The proline sandwich configuration represents a key contact point between P329 on the Fc (red) and 2 tryptophan residues on FcγRIII (blue; PBD 1E4K). c) Side-chain interactions of glycan residues with their respective amino acids. Individual glycan:amino acid interactions are indicated in red. The ring structure of F241 rotates ~90° in the structure of a sialylated Fc. d) Schematic view of the principal glycosylation structures attached to Asn 297 of the Fc. The core glycan structure within the rectangle shows the invariable heptasaccharide group conjugated to the Fc. Sugars beyond the core are attached with varying frequencies. GlcNAc, N-Acetylglucosamine; Fuc, Fucose; Man, Mannose; Gal, Galactose; Sial, N-Acetylneuraminic Acid (sialic acid).

Figure 3.. Immunomodulatory functions of Type-I and Type-II FcRs

a) Antigen presentation. Antibodies bind to soluble antigens to form immune complexes. Recognition of immune complexes by Type-I activating FcyRs expressed on DCs results in the engulfment of the complex by endocytosis and DC maturation, including the upregulation of MHC costimulatory molecules. The internalized antigens are processed and presented on MHC class I and MHC class II molecules to CD4⁺ and CD8⁺ T cells, resulting in their activation to mediate specific effector functions. b) B cell selection. Selection of B cells with high affinity B cell receptors occurs in the germinal center. FDCs express the inhibitory receptor FcyRIIB, which binds immune complexes and presents them to germinal center B cells. The Type-I Fc-receptor FcyRIIB and the Type-II Fc-receptor CD23 are also expressed on the cell surface of GC B cells, facilitating immune complex binding. Preferential antigen binding by the B cell receptor results in the positive selection of the respective B cells, enabling them to further differentiate into antibody producing plasma cells or memory B cells. By contrast, exclusive binding of the presented immune complex via the inhibitory FcyRIIB leads to the induction of apoptosis, thereby setting a threshold for the selection of B cells with high affinity B cell receptors. Further, since sialylated immune complexes may also interact with CD23 on GC B cells, regulation of Fc glycosylation may provide a means to modulate cell activation and/or affinity maturation in an as-yet uncharacterized novel pathway.

Figure 4.. Type-I FcR-mediated effector functions.

a) Antibody-dependent enhancement of infection and/or disease. Pre-existing sub-neutralizing antibodies present from a primary infection (e.g., dengue) bind to viral particles during a secondary infection with a different viral serotype. These immune complexes are bound by Type-I activating FcγR expressed on monocytes and macrophages, mediating increased virus uptake and replication that results in the enhancement of infection. b) Clearance/cytotoxicity of antibody-coated pathogen, infected/neoplastic cells, or regulatory T cells. Antibody-opsonized pathogens interact with Type-I activating FcγRs on monocytes/macrophages, leading to phagocytosis and clearance. Antibody-coated malignant, virally-infected, or regulatory T cells also engage monocytes/macrophages or NK cells, resulting in phagocytosis or cell-mediated cytotoxicity (ADCC) of the target cell. Removal of infected/tumor cells leads to clearance of disease, while removal of regulatory T cells leads to enhanced cellular immunity. c) Anti-TNFR family agonistic effect requires Type-I FcγRIIb expression. Anti-TNFR family antibody (e.g., anti-CD40) binds CD40 on antigen-presenting cells. FcγRIIb⁺ cells bind CD40-bound antibody in trans, thereby acting as a scaffold to provide the clustering of TNFR molecules on the membrane to mimic the effect of multimeric ligand engagement and activate TNFR-related pathways (CD40 signaling and cellular activation).

Figure 5.. Both Type-I and Type-II Fc-receptors mediate the anti-inflammatory effects of IVIG or sialylated IgG.

Immune complexes between autoantibodies and autoantigens crosslink Type-I activating FcγRs promoting the activation of macrophages and inflammatory autoimmune disease. Sialylated Fcs engage DC-SIGN/SIGN-RI⁺ macrophages or DCs, promoting IL-33 expression. This IL-33 signlas activated FcɛRI+ innate leukocytes (basophils) to produce IL-4. IL-4, in turn, promotes upregulation of FcγRIIB on effector macrophages, thereby increasing the activation threshold required to trigger inflammation. Alternatively, as-yet unidentified Type-II FcRs expressed by various cell types may also mediate the anti-inflammatory effects of IVIG or sialylated IgG through unidentified pathways, depending on the type and location of the inflammation.WWW