CD16A

Official Full Name

Fc gamma receptor IIIa

Organism

Homo sapiens

GeneID

2214

Background

This gene encodes a receptor for the Fc portion of immunoglobulin G, and it is involved in the removal of antigen-antibody complexes from the circulation, as well as other responses, including antibody dependent cellular mediated cytotoxicity and antibody dependent enhancement of virus infections. This gene (FCGR3A) is highly similar to another nearby gene (FCGR3B) located on chromosome 1. The receptor encoded by this gene is expressed on natural killer (NK) cells as an integral membrane glycoprotein anchored through a transmembrane peptide, whereas FCGR3B is expressed on polymorphonuclear neutrophils (PMN) where the receptor is anchored through a phosphatidylinositol (PI) linkage. Mutations in this gene are associated with immunodeficiency 20, and have been linked to susceptibility to recurrent viral infections, susceptibility to systemic lupus erythematosus, and alloimmune neonatal neutropenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

Synonyms

FCGR3A; CD16; FCG3; CD16A; FCGR3; IGFR3; IMD20; FCR-10; FCRIII; CD16-II; FCGRIII; FCRIIIA; FcGRIIIA;

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Detailed Information

CD16A, encoded by the FCGR3A gene, is a key member of the immunoglobulin G (IgG) Fc receptor family and is located on human chromosome 1q23.3. This region constitutes a highly homologous and complex gene cluster containing multiple Fcγ receptor genes. Among them, FCGR3A and FCGR3B share high sequence similarity but differ significantly in expression patterns, membrane anchoring mechanisms, and functional properties.

The FCGR3A gene encodes CD16A, a transmembrane glycoprotein comprising an extracellular domain that binds the IgG Fc portion, a single transmembrane segment, and an intracellular domain. The intracellular domain itself lacks signaling motifs and requires association with homodimeric or heterodimeric adaptor proteins containing immunoreceptor tyrosine-based activation motifs (ITAMs) to initiate downstream signaling. CD16A expression is primarily restricted to natural killer (NK) cells, macrophages, and a small subset of T cells, indicating its central role in specific immune responses. In contrast, FCGR3B encodes CD16B, which is glycosylphosphatidylinositol (GPI)-anchored on neutrophils, and this anchoring difference profoundly influences signaling and functional regulation.

Biological Significance

CD16A serves as a bridge between humoral and cellular immunity, mediating antibody-dependent cellular cytotoxicity (ADCC) to eliminate pathogen-infected or transformed target cells. CD16A exhibits low affinity for monomeric IgG, preventing nonspecific activation of immune cells in the absence of antigen. However, when infection or tumorigenesis leads to dense antigen–IgG complexes on target cells, CD16A efficiently binds these Fc clusters, triggering receptor clustering and potent activation signaling.

Figure 1. CD16a⁺ NK cells and nonclassical monocytes correlate with kidney allograft rejection severity. (Perkins GB, et al., 2024)

On NK cells, CD16A associates non-covalently with adaptor proteins such as CD3ζ and FCER1γ chains. Upon receptor crosslinking, Src-family kinases phosphorylate ITAMs on adaptor proteins, recruiting and activating Syk kinase, which in turn signals through PI3K and PLCγ pathways, elevating intracellular Ca²⁺, reorganizing the cytoskeleton, and driving degranulation of perforin and granzymes, along with secretion of cytokines like interferon-γ, leading to efficient target cell lysis.

Beyond ADCC, CD16A profoundly influences NK cell development, homeostasis, and functional shaping. Its signaling is crucial for survival of NK progenitors, apoptosis inhibition, and induction of memory-like adaptive NK cells, which exhibit enhanced and rapid responses upon re-encountering antigens. In myeloid cells such as macrophages, CD16A activation similarly triggers inflammatory cytokine release and ADCC effects, although signaling may vary depending on adaptor composition. Notably, CD16A also mediates antibody-dependent enhancement (ADE) in viral infections such as dengue, where subneutralizing IgG-virus complexes bind CD16A on myeloid cells, facilitating viral entry and replication, exacerbating disease.

Clinical Relevance

CD16A is clinically significant in two key areas: as a critical effector in therapeutic monoclonal antibody (mAb) therapy and as a genetic determinant of treatment efficacy and disease susceptibility. Most IgG1-based anti-cancer mAbs act, in part, by engaging CD16A on effector cells, recruiting NK cells and macrophages for target elimination. Therefore, CD16A expression and function directly impact therapeutic outcomes.

A functional single-nucleotide polymorphism (SNP) at residue 158 of FCGR3A results in either valine (V) or phenylalanine (F). The V allele exhibits significantly higher affinity for IgG1 and IgG3 Fc regions compared to the F allele, translating into enhanced ADCC. Clinical studies confirm that patients with the FCGR3A-158VV genotype display higher response rates and longer progression-free survival following treatment with rituximab or trastuzumab. This genetic insight has driven next-generation antibody engineering, such as afucosylated antibodies with enhanced CD16A binding, showing superior tumor clearance in preclinical and clinical settings.

In autoimmune diseases, FCGR3A polymorphisms are associated with susceptibility to conditions like systemic lupus erythematosus, likely through effects on immune complex clearance and modulation of immune cell activation thresholds. In infectious diseases, CD16A-mediated ADE represents a safety concern in dengue vaccines and antibody therapies.

Future CD16A-targeted immunotherapies may extend beyond leveraging endogenous NK cells, including bispecific antibodies targeting CD16A or CAR-NK cells expressing CD16A, offering more precise and potent tumor targeting.

References

Bruhns P, Iannascoli B, England P, et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2009;113(16):3716–3725.
Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol. 2013;6:1.
Lee YH, Song GG. Association between functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases: a meta-analysis. Pharmacogenomics J. 2023 Nov;23(6):210-216.
Perkins GB, Zuiani JD, Coates PT. The innate immune cells at the heart of kidney allograft rejection. Kidney Int. 2024 Sep;106(3):348-350.

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