Fc receptor, IgG, low affinity IV (FcγRIV)

Fc receptor, IgG, low affinity IV (FcγRIV), also known as CD16-2, is an activating cell surface receptor primarily expressed on murine myeloid cells such as macrophages, neutrophils, and dendritic cells. It acts as a bridge between the adaptive and innate immune systems by selectively recognizing and binding to the Fc regions of IgG2a and IgG2b antibody subclasses with intermediate to high affinity. Upon ligation by immune complexes, FcγRIV associates with the common Fc receptor γ-chain to initiate signaling cascades that drive essential effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. In disease contexts, FcγRIV is a critical mediator of inflammatory damage in autoimmune models, such as rheumatoid arthritis and systemic lupus erythematosus, and has recently been implicated in the pathogenesis of immune checkpoint inhibitor-induced myocarditis. Although it is a mouse-specific protein, it is considered the functional ortholog of the human FCGR3A (CD16a) receptor, making it a pivotal target for evaluating the efficacy and safety of therapeutic antibodies in preclinical mouse models. Understanding its regulation and activity is essential for optimizing antibody-based therapies and managing potentially harmful inflammatory responses.

Other names

CD16-2Fcgr4FcgRIVFcgammaRIVFc receptor-like 3Fcrl34833442P21Rik

FcγRIV functions as an activating receptor that requires association with the common Fc receptor gamma (FcRγ) chain dimer for surface expression and signaling. Binding to the Fc region of multivalent IgG2a or IgG2b immune complexes induces the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within the γ-chain. This phosphorylation recruits Syk family kinases, which trigger downstream signaling pathways (e.g., PLCγ, PI3K) that lead to the activation of effector cells, the release of inflammatory mediators, and the destruction of target cells through ADCC or phagocytosis.