Fcγ Receptor Function and the Design of Vaccination Strategies

Abstract

Through specific interactions with distinct types of Fcγ receptors (FcγRs), the Fc domain of immunoglobulin G (IgG) mediates a wide spectrum of immunological functions that influence both innate and adaptive responses. Recent studies indicate that IgG Fc-FcγR interactions are dynamically regulated during an immune response through the control of the Fc-associated glycan structure and Ig subclass composition on the one hand and selective FcγR expression on immune cells on the other, which together determine the capacity of IgG to interact in a cell-type-specific manner with specific members of the FcγR family. Here, we present a framework that synthesizes the current understanding of the contribution of FcγR pathways to the induction and regulation of antibody and T cell responses. Within this context, we discuss vaccination strategies to elicit broad and potent immune responses based on the immunomodulatory properties of Fc-FcγR interactions.

Keywords: antibodies; effector functions; immune regulation; immunity; immunization; therapy; vaccination.

Figure 1. Overview of the expression pattern of type I and type II FcγRs in leukocyte populations

Both type I and type II FcγRs exhibit a distinct pattern of cellular expression among the various leukocyte types, with different cell subsets typically co-expressing more than one FcγR type at any one time. The expression of several FcγR genes fluctuates throughout leukocyte development and differentiation and can be regulated by cytokines and chemokines present at sites of inflammation, tissue injury and infection. Alterations in the FcγR expression pattern readily influences the outcome of FcγR-mediated signaling and has profound consequences on the immunomodulatory functions initiated upon FcγR crosslinking by IgG immune complexes.

Figure 2. The role of FcγR-mediated signaling in the regulation of dendritic cell function and T cell responses

Human dendritic cells (DCs) express two classes of type I FcγRs: FcγRIIa and FcγRIIb with activating or inhibitory signaling activities, respectively. The opposing signaling activities of these FcγRs is a key homeostatic mechanism that regulates DC function and T-cell activation. Engagement of FcγRIIb by IgG immune complexes fails to induce DC maturation, as pro-inflammatory signals from FcγRIIa are counterbalanced by FcγRIIb. In contrast, preferential engagement of FcγRIIa stimulates DC activation, leading to enhanced antigen presentation, the release of pro-inflammatory chemokines and cytokines, and T-cell activation and expansion.