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.