FcRIIIA

Fc gamma receptor IIIa (FcγRIIIa), also known as CD16a, is a receptor for the Fc portion of immunoglobulin G (IgG) and a member of the Fc gamma receptor family. It is a low-affinity receptor that primarily recognizes IgG1 and IgG3 and plays a key role in antibody-dependent cellular cytotoxicity (ADCC). In humans, FcγRIIIa is encoded by the FCGR3A gene and functions as a transmembrane protein that associates with the FcR gamma chain to initiate signaling via immunoreceptor tyrosine-based activation motifs (ITAMs).

Expression and structure: FcγRIIIa is expressed mainly on natural killer (NK) cells and to a lesser extent on certain macrophages, dendritic cells, and some T cells. The receptor binds IgG Fc regions and relies on the FcR gamma chain for signal transduction. It is distinct from FcγRIIIb (CD16b), which is GPI-anchored and found on neutrophils.

Function: Engagement of FcγRIIIa by IgG-coated targets activates NK cells, triggering degranulation and release of cytotoxic molecules, contributing to ADCC. The receptor also participates in antigen presentation and cytokine production in certain contexts. Affinity for IgG can be influenced by IgG subclass and by genetic variations.

Genetic polymorphism: A well-known polymorphism in FCGR3A is at position 158, resulting in valine (V) or phenylalanine (F). The V158 variant has higher affinity for IgG1 and IgG3, a difference that can affect clinical responses to monoclonal antibody therapies such as rituximab, cetuximab, and trastuzumab in various cancers.

Clinical relevance: FcγRIIIa-mediated ADCC contributes to the therapeutic efficacy of several monoclonal antibodies. FCGR3A genotype may partially predict response, though outcomes depend on multiple factors including antibody glycosylation, receptor expression, and immune context.