FCGR3A: A Key Receptor for Immune Regulation

2. Molecular Structure, Expression Regulation, and Ligand Interaction

2.1 Structure of FCGR3A

FCGR3A belongs to the IgG Fc receptor family. The gene is located on the long arm of chromosome 1 (1q23) and encodes a type I transmembrane glycoprotein of approximately 50 - 65 kDa. It consists of two extracellular Ig-like domains, a single transmembrane region, and an intracellular tail.

Its intracellular region contains an Immunoreceptor Tyrosine-based Activation Motif (ITAM). By binding to the Fc region of IgG, it triggers a downstream signaling cascade, mediating Antibody-Dependent Cellular Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP) ^[2].

This figure elucidates the mechanisms by which CD16A and NKp46 receptors enhance NK cell functions.

Source: PMID: 39513028

The extracellular domain binds to the Fc region of IgG (especially IgG1 and IgG3 subclasses) with high affinity, triggering receptor cross-linking and signal transduction. Although the intracellular segment lacks intrinsic enzymatic activity, it recruits Syk or ZAP70 kinases via the ITAM, initiating downstream signaling cascades that promote cell activation, granzyme release, and cytokine secretion ^[3].

2.2 Expression and Regulation in Immune Cells

FCGR3A (CD16A) is primarily expressed in NK cells, subsets of monocytes/macrophages, and certain T cells. Its expression levels and functional regulation are closely related to immune responses.

NK Cells: FCGR3A is the key receptor mediating ADCC. Its surface density is influenced by genetic polymorphisms (such as FCGR3A-158V/F). The 158V allele is associated with higher receptor expression and ADCC activity.

Monocytes/Macrophages: Subsets with high FCGR3A expression are significantly enriched in kidney transplant rejection and the tumor microenvironment (TME), participating in antibody-mediated innate immune activation ^[4].

Regulation: FCGR3A expression is regulated by ADAM17-mediated proteolytic shedding, rapidly downregulating after leukocyte activation to limit excessive inflammatory responses ^[5]. T Cells: The CD8+CD11b+ subset can co-express FCGR3A and IL-2Rβ.

Tumor Microenvironment: High FCGR3A expression correlates with M2 macrophage infiltration and the upregulation of immune checkpoint molecules (such as PD-L1), suggesting a role in tumor immune escape.

2.3 Major Ligands

The core ligand of FCGR3A is the Fc region of IgG. Binding affinity is regulated by IgG glycosylation modifications (such as core fucosylation) and receptor polymorphisms.

Activation: Upon receptor cross-linking, phosphorylation of the ITAM motif recruits Syk kinase, activating the PLCγ, PI3K, and MAPK pathways. This promotes calcium influx, cytoskeletal rearrangement, and the release of effector molecules (Granzyme B, Perforin).

Synergy: FCGR3A signaling synergizes with Toll-like Receptor (TLR) or cytokine receptor signaling to enhance immune cell activation.

3. Signal Transduction and Immune Effector Mechanisms

3.1 Signal Transduction Pathways

ITAM-Dependent Activation: IgG binding → Src kinase-mediated ITAM phosphorylation → Syk kinase cascade → PI3K-Akt and PLCγ pathways.

PLCγ: Promotes IP3 production → Calcium influx → NFAT activation.

PI3K-Akt: Enhances cell metabolism and survival via the mTOR pathway.

Non-Canonical Regulation: In NK cells, FCGR3A synergizes with NKp46, amplifying signals through CD3ζ and FcRγ chains to promote cytokine release (IFN-γ, TNF-α) and cytotoxicity. In certain scenarios, the ITAM can exhibit a "dual nature" (ITAMi/ITAMa)—inhibiting signals upon monomeric binding but activating them upon multimeric cross-linking ^[6].

3.2 Immune Effector Mechanisms

Anti-Tumor Immunity: NK cells with high FCGR3A expression eliminate antibody-coated tumor cells via ADCC. Activity positively correlates with the high-affinity FCGR3A-V158 genotype. Bispecific antibodies (e.g., NK cell engagers) enhance killing by simultaneously targeting FCGR3A and tumor antigens (e.g., CD19).

Modalities of NKG2DL-based immunotherapy in AML.

Source: PMID: 36555547

Anti-Infection Defense: Monocytes/macrophages clear IgG-opsonized pathogens (HIV, bacteria) via phagocytosis. IgG from HIV "Viral Controllers" shows stronger FCGR3A activation.

Inflammation: Excessive activation may lead to platelet aggregation (e.g., Heparin-Induced Thrombocytopenia) or tissue damage. High FCGR3A expression drives cytokine release (IL-12) in transplant rejection.