Dissecting FcγR Regulation through a Multivalent Binding Model

Abstract

Many immune receptors transduce activation across the plasma membrane through their clustering. With Fcγ receptors (FcγRs), this clustering is driven by binding to antibodies of differing affinities that are in turn bound to multivalent antigen. As a consequence of this activation mechanism, accounting for and rationally manipulating immunoglobulin (Ig)G effector function is complicated by, among other factors, differing affinities between FcγR species and changes in the valency of antigen binding. In this study, we show that a model of multivalent receptor-ligand binding can effectively account for the contribution of IgG-FcγR affinity and immune complex valency. This model in turn enables us to make specific predictions about the effect of immune complexes of defined composition. In total, these results enable both rational immune complex design for a desired IgG effector function and the deconvolution of effector function by immune complexes.

There Is (Scientific) Strength in Numbers: A Comprehensive Quantitation of Fc Gamma Receptor Numbers on Human and Murine Peripheral Blood Leukocytes

“…This led to the development of the concept of the so called A/I ratio as a prediction of the outcome of binding of IgG molecules of a given isotype based on its affinities to the inhibitory and activating receptors, respectively (13)(14)(15). Based on the A/I ratio concept mathematical models have been developed predicting IgG activity (16). However, it is to be expected that other factors such as the avidity of the immune complex which is influenced by the number of immunoglobulins bound to the antigen and the number of activating and inhibitory receptors on the surface of the respective effector cell may influence IgG effector functions (17).…”

Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation

“…In summary, these findings indicate that IgG-ICs are able to differentially engage an array of FcγRs and preferentially cross-link low affinity receptors FcγRIIA, IIIA, and IIB, which under serum conditions are considered the main effector FcγRs on immune cells. In addition to the different affinities of FcγRs for IgG isotypes, the IgG-IC size plays an important role in the binding to FcγRs (35,42,43). Using ICs of defined sizes, the authors demonstrated that for ICs composed of IgG2 and IgG4, larger ICs exhibit increased interaction with the low-affinity human FcγRs over smaller ICs (42).…”

Multiple Variables at the Leukocyte Cell Surface Impact Fc γ Receptor-Dependent Mechanisms

“…Moreover, the binding patterns were comparable to experiments using primary leukocytes that increased cytokine secretion in response to larger immune complexes. These data led to a mathematical model that describes effects of valency and IgG subclass on in vivo function (135). The differential binding due to a change in the size of immune complex can potentially lead to substantial changes in cell signaling and recent technical advances provide a means to quantitate signaling with cell-based assays (136).…”