Impact of Plasma Membrane Domains on IgG Fc Receptor Function

Abstract

Lipid cell membranes not only represent the physical boundaries of cells. They also actively participate in many cellular processes. This contribution is facilitated by highly complex mixtures of different lipids and incorporation of various membrane proteins. One group of membrane-associated receptors are Fc receptors (FcRs). These cell-surface receptors are crucial for the activity of most immune cells as they bind immunoglobulins such as immunoglobulin G (IgG). Based on distinct mechanisms of IgG binding, two classes of Fc receptors are now recognized: the canonical type I FcγRs and select C-type lectin receptors newly referred to as type II FcRs. Upon IgG immune complex induced cross-linking, these receptors are known to induce a multitude of cellular effector responses in a cell-type dependent manner, including internalization, antigen processing, and presentation as well as production of cytokines. The response is also determined by specific intracellular signaling domains, allowing FcRs to either positively or negatively modulate immune cell activity. Expression of cell-type specific combinations and numbers of receptors therefore ultimately sets a threshold for induction of effector responses. Mechanistically, receptor cross-linking and localization to lipid rafts, i.e., organized membrane microdomains enriched in intracellular signaling proteins, were proposed as major determinants of initial FcR activation. Given that immune cell membranes might also vary in their lipid compositions, it is reasonable to speculate, that the cell membrane and especially lipid rafts serve as an additional regulator of FcR activity. In this article, we aim to summarize the current knowledge on the interplay of lipid rafts and IgG binding FcRs with a focus on the plasma membrane composition and receptor localization in immune cells, the proposed mechanisms underlying this localization and consequences for FcR function with respect to their immunoregulatory capacity.

Engineered IgG1-Fc Molecules Define Valency Control of Cell Surface Fcγ Receptor Inhibition and Activation in Endosomes

“…The motions of the Fc constructs displayed similar proportions of each motion class and could be observed transitioning between classes (frequently between confined and free diffusion, dark blue to or from light blue, Figure 3A ). These motion types are consistent with Fc-FcγR complexes interacting with actin corrals, lipid rafts, and protein islands ( 27 – 30 ). As predicted by the lack of Syk recruitment, only small differences in diffusion constants and types of motions were observed across rFc, SIF1 and PentX ( Figure 4B ).…”

Site-Specific Glycosylation Mapping of Fc Gamma Receptor IIIb from Neutrophils of Individual Healthy Donors

“… 16 FcγRIIIb seems to affect signaling of other Fc receptors by accumulating in lipid rafts, which are enriched in kinases (Src) and are required for ITAM phosphorylation and signaling. 17 Given the relatively high expression levels of FcγRIIIb on neutrophils with 120 000–300 000 copies per cell, 18 and the dominance of neutrophils among white blood cells, FcγRIIIb can be considered to be the most abundant FcγR in circulation. Known functions include activation of neutrophil degranulation, cell adhesion, calcium mobilization, and neutrophil tethering to soluble immune complexes.…”

IgG Subclasses Shape Cytokine Responses by Human Myeloid Immune Cells through Differential Metabolic Reprogramming

“…Interestingly, we identified even more diversity in IgG-induced signaling by showing that the activation of FcgRIIa by the same subclass can lead to the activation of different intracellular pathways because IgG2 enhanced the glycolytic rate upon costimulation with TLR2 but lowered the glycolysis upon costimulation with TLR3. Yet, although blocking of FcgRIIa completely abrogated IgG-induced cytokine responses, a role for nonclassical Fc receptors such as C-type lectin receptors cannot be ruled out because these receptors simultaneously recognize the Abs and are also capable of inducing signaling and metabolic pathways (43). Particularly, dectin-1 is an interesting candidate in this regard because it is expressed by myeloid immune cells, is known to synergize with TLR activation (44), and can also signal through Syk and IRF5 (45).…”