Fig 3. A/I ratio dictates the outcome of Fc-effector function of IgG antibodies
FcγRs can be either inhibitory (FcγRIIb) with immunoreceptor tyrosine-based inhibition motif (ITIM) or activating (FcγRI, FcγRIIa/IIc, FcγRIIIa, FcγRIIIb)11. Activating FcγRI and IIIa are associated with the common FcR gamma chain dimer containing two ITAMs (immunoreceptor tyrosine-based activating motifs); FcγRIIa and IIc are not associated with the gamma chain, but contain their own ITAM motif, whereas FcγRIIIb does not contain an ITAM motif and is not always considered as an activating receptor11. Expressed mostly on neutrophils, FcγRIIIb has been shown to favor phagocytosis (ADCP) in cooperation with FcγRIIa, but, on the other hand, it has a negative impact on neutrophilic ADCC by acting as a decoy receptor for IgG, thus competing with FcγRIIa for antibody binding10.
Crosslinking of an activating receptor with the inhibiting receptor results in downregulation of the activating signal. Therefore, all activating FcγRs are counter-balanced by one inhibiting receptor FcγRIIb. Differential affinity of IgG for FcRs is defined as activating-to-inhibitory (A/I) ratio and varies across IgG subclasses. IgG subclasses with high A/I ratio (IgG1, IgG3) exert potent effector functions desirable for depleting antibodies, whereas low A/I ratio (IgG2, IgG4) is preferred when Fc-mediated cell depletion is unwanted.