FcRIII

FcRIII, or Fc gamma receptor III, is a member of the Fc receptor family that binds the Fc portion of IgG antibodies. In humans, FcγRIII exists primarily in two isoforms: FcγRIIIa (CD16a) and FcγRIIIb (CD16b).

FcγRIIIa is a transmembrane receptor expressed mainly on natural killer (NK) cells and on subsets of macrophages and dendritic cells. FcγRIIIb is a glycosylphosphatidylinositol (GPI)-anchored protein expressed predominantly on neutrophils and, to a lesser extent, on other leukocytes. Both isoforms preferentially bind IgG1 and IgG3, with FcγRIIIa mediating functional responses through signaling.

Signaling and function: FcγRIIIa couples to the Fc receptor gamma chain containing an immunoreceptor tyrosine-based activation motif (ITAM). Engagement by IgG-containing immune complexes activates NK cells and triggers antibody-dependent cellular cytotoxicity (ADCC). FcγRIIIb, lacking a cytoplasmic signaling motif, is thought to participate in immune complex handling and neutrophil activation by cooperating with other receptors.

Genetics and clinical relevance: The FCGR3A gene encodes FcγRIIIa, and FCGR3B encodes FcγRIIIb. A common polymorphism in FCGR3A (V158F) affects affinity for IgG1 and IgG3 and has been linked to variability in clinical responses to therapeutic antibodies such as rituximab and cetuximab. Copy number variation at FCGR3B can influence neutrophil-mediated responses and susceptibility to certain autoimmune conditions.

Therapeutic relevance: Many monoclonal antibodies rely on FcγRIII–mediated ADCC for efficacy. Engineering the Fc region to increase FcγRIIIa binding can enhance therapeutic activity, while blockade of FcγRIII signaling is explored to reduce inflammation in autoimmune disease.