Abstract
Antibody dependent cellular cytotoxicity (ADCC) is an Fc-dependent effector function of IgG important for anti-viral immunity and anti-tumor therapies. NK-cell mediated ADCC is mainly triggered by IgG-subclasses IgG1 and IgG3 through the IgG-Fc-receptor (FcγR) IIIa. Polymorphisms in the immunoglobulin gamma heavy chain gene likely form a layer of variation in the strength of the ADCC-response, but this has never been studied in detail. We produced all 27 known IgG allotypes and assessed FcγRIIIa binding and ADCC activity. While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3. ADCC capacity was affected by residues 291, 292, and 296 in the CH2 domain through altered affinity or avidity for FcγRIIIa. Furthermore, allotypic variation in hinge length affected ADCC, likely through altered proximity at the immunological synapse. Thus, these functional differences between IgG allotypes have important implications for therapeutic applications and susceptibility to infectious-, allo- or auto-immune diseases.
Highlights
In the defense against invading pathogens, Immunoglobulins are formed by B cells
To study the influence of IgG polymorphisms on the Antibody dependent cellular cytotoxicity (ADCC) activity, all polymorphic variant constant domains described previously were paired with variable domains with anti-RhD specificity or anti-TNP specificity and expressed in HEK293F cells with the corresponding light chain [42,43,44]
Consistent with previous studies, the affinity of IgG1 and IgG3 allotypes for FcγRIIIa was highly dependent on the polymorphic variant of FcγRIIIa with the V158 variant binding with significantly higher affinity [18, 20, 51] (Figures 2D,E)
Summary
In the defense against invading pathogens, Immunoglobulins are formed by B cells. These bind the pathogen via their Fab domains and subsequently activate both complement and immune cells by immunoglobulin Fc-receptors [1]. The largest portion are Immunoglobulin γ (IgG) antibodies that mediate their effector functions through Fc gamma receptors (FcγR) on myeloid and Natural Killer (NK) cells [2,3,4]. NK cells mediate ADCC through binding of antibody opsonized target cells by membrane expressed FcγRIIIa and induce cytotoxicity by releasing granzymes and perforins stored in intracellular granules [7, 8]. This is an important effector mechanism that contributes to the killing of tumor cells upon immunotherapy [9, 10]
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