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.
Highlights
fragment crystallizable (Fc) receptors (FcR) for immunoglobulin G (IgG) are cell surface receptors widely expressed on cells of both, the innate and the adaptive immune system
Based on distinct mechanisms of IgG binding, these IgG FcRs are currently classified as either type I Fc receptors or type II FcRs, which belong to the sugar-binding C-type lectin receptors [reviewed in [1]]
Lateral heterogeneity of membranes including the formation of organized microdomains, i.e., lipid rafts, have previously been shown to affect a number of receptors expressed on immune cells
Summary
Fc receptors (FcR) for immunoglobulin G (IgG) are cell surface receptors widely expressed on cells of both, the innate and the adaptive immune system. In comparison to type I FcRs, information about the role of membrane domains on type II FcR localization and function is scarce When it comes to pathogen recognition, signaling and the production of anti-microbial mediators such as reactive oxygen species via pattern recognition receptors, a phagocytic cell has to distinguish between soluble antigens released by pathogens in the distance and direct contact. As Dectin-1 was found to associate with FcγRIIb upon IgG immune complex binding [146] and FcγRIIb is localized to lipid rafts upon ligand-induced cross-linking [195] this further points toward an important role of organized microdomains for Dectin-1 activity. More research identifying these potential systemic drug side-effects will be required to understand this in more detail in the future
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