An Fc receptor is a protein found on the surface of certain cells – including, among others,
B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils,
eosinophils, basophils and mast cells – that contribute to the protective functions
of the immune system.
Its name is derived from its binding specificity for a part of an antibody known as the Fc
region.
Fc receptors bind to antibodies that are attached to infected cells or invading pathogens.
Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells
by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity.
Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism
known as antibody-dependent enhancement of infection.
Classes of Fc receptor There are several different types of Fc receptors,
which are classified based on the type of antibody that they recognize.
The Latin letter used to identify a type of antibody is converted into the corresponding
Greek letter, which is placed after the 'Fc' part of the name.
For example, those that bind the most common class of antibody, IgG, are called Fc-gamma
receptors, those that bind IgA are called Fc-alpha receptors and those that bind IgE
are called Fc-epsilon receptors.
Fc-gamma receptors All of the Fcγ receptors belong to the immunoglobulin
superfamily and are the most important Fc receptors for inducing phagocytosis of opsonized
microbes.
This family includes several members, FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB,
which differ in their antibody affinities due to their different molecular structure.
For instance, FcγRI binds to IgG more strongly than FcγRII or FcγRIII does.
FcγRI also has an extracellular portion composed of three immunoglobulin-like domains, one
more domain than FcγRII or FcγRIII has.
This property allows FcγRI to bind a sole IgG molecule, but all Fcγ receptors must
bind multiple IgG molecules within an immune complex to be activated.
Another FcR is expressed on multiple cell types and is similar in structure to MHC class
I.
This receptor also binds IgG and is involved in preservation of this antibody.
However, since this Fc receptor is also involved in transferring IgG from a mother either via
the placenta to her fetus or in milk to her suckling infant, it is called the neonatal
Fc receptor.
Recently, research suggested that this receptor plays a role in the homeostasis of IgG serum
levels.
Fc-alpha receptors Only one Fc receptor belongs to the FcαR
subgroup, which is called FcαRI.
FcαRI is found on the surface of neutrophils, eosinophils, monocytes, some macrophages,
and some dendritic cells.
It is composed of two extracellular Ig-like domains, and is a member of both the immunoglobulin
superfamily and the multi-chain immune recognition receptor family.
It signals by associating with two FcRγ signaling chains.
Another receptor can also bind IgA, although it has higher affinity for another antibody
called IgM.
This receptor is called the Fc-alpha/mu receptor and is a type I transmembrane protein.
With one Ig-like domain in its extracellular portion, this Fc receptor is also a member
of the immunoglobulin superfamily.
Fc-epsilon receptors Two types of FcεR are known:
the high-affinity receptor FcεRI is a member of the immunoglobulin superfamily.
FcεRI is found on epidermal Langerhans cells, eosinophils, mast cells and basophils.
As a result of its cellular distribution, this receptor plays a major role in controlling
allergic responses.
FcεRI is also expressed on antigen-presenting cells, and controls the production of important
immune mediators called cytokines that promote inflammation.
the low-affinity receptor FcεRII is a C-type lectin.
FcεRII has multiple functions as a membrane-bound or soluble receptor; it controls B cell growth
and differentiation and blocks IgE-binding of eosinophils, monocytes, and basophils.
Summary table Functions of Fc receptors
Fc receptors are found on a number of cells in the immune system including phagocytes
like macrophages and monocytes, granulocytes like neutrophils and eosinophils, and lymphocytes
of the innate immune system or adaptive immune system.
They allow these cells to bind to antibodies that are attached to the surface of microbes
or microbe infected cells, helping these cells to identify and eliminate microbial pathogens.
The Fc receptors bind the antibodies at their Fc region, an interaction that activates the
cell that possesses the Fc receptor.
Activation of phagocytes is the most common function attributed to Fc receptors.
For example, macrophages begin to ingest and kill an IgG-coated pathogen by phagocytosis
following engagement of their Fcγ receptors.
Another process involving Fc receptors is called antibody-dependent cell-mediated cytotoxicity.
During ADCC, FcγRIII receptors on the surface of natural killer cells stimulate the NK cells
to release cytotoxic molecules from their granules to kill antibody-covered target cells.
FcεRI has a different function.
FcεRI is the Fc receptor on granulocytes, that is involved in allergic reactions and
defense against parasitic infections.
When an appropriate allergic antigen or parasite is present, the cross-linking of a least two
of IgE molecules and their Fc receptors on the surface of a granulocyte will trigger
the cell to rapidly release preformed mediators from its granules.
Signaling mechanisms of Fc receptors Fc gamma receptors generate signals within
their cells through an important activation motif known as an Immunoreceptor tyrosine-based
activation motif.
An ITAM is a specific sequence of amino acids occurring twice in close succession in the
intracellular tail of a receptor.
When phosphate groups are added to the tyrosine residue of the ITAM by enzymes called tyrosine
kinases, a signaling cascade is generated within the cell.
This phosphorylation reaction typically follows interaction of an Fc receptor with its ligand.
An ITAM is present in the intracellular tail of FcγRIIA, and its phosphorylation induces
phagocytosis in macrophages.
FcγRI and FcγRIIIA do not have an ITAM but can transmit an activating signal to their
phagocytes by interacting with another protein that does.
This adaptor protein is called the Fcγ subunit and, like FcγRIIA, contains the two YXXL
sequences that are characteristic of an ITAM.
The presence of only one YXXL motif is not sufficient to activate cells, and represents
a motif known as an immunoreceptor tyrosine-based inhibitory motif.
FcγRIIB1 and FcγRIIB2 have an ITIM sequence and are inhibitory Fc receptors; they do not
induce phagocytosis.
Inhibitory actions of these receptors are controlled by enzymes that remove phosphate
groups from tyrosine residues; the phosphatases SHP-1 and SHIP-1 inhibit signaling by Fcγ
receptors.
Binding of ligand to FcγRIIB leads to phosphorylation of the tyrosine of the ITAM motif.
This modification generates the binding site for the phosphatase, a SH2 recognition domain.
The abrogation of ITAM activation signaling is caused by inhibition of protein tyrosine
kinases of Src family, and by hydrolyzing the membrane PIP3 interrupting the further
downstream signaling by the activating receptors, such as activating FcγRs, TCR, BCR and cytokine
receptors.
The negative signaling by FcγRIIB is mainly important for regulation of activated B cells.
The positive B cell signaling is initiated by binding of foreign antigen to surface immunoglobulin.
The same antigen-specific antibody is secreted and it can feedback-suppress, or promote negative
signaling.
This negative signaling is being provided by FcγRIIB.: Experiments using B cell deletion
mutants and dominant-negative enzymes have firmly established an important role for SH2-domain-containing
inositol 5-phosphatase in negative signaling.
Negative signaling through SHIP appears to inhibit the Ras pathway through SH2 domain
competition with Grb2 and Shc and may involve consumption of intracellular lipid mediators
that act as allosteric enzyme activators or that promote entry of extracellular Ca2+.
Cellular activation by Fc Receptors
Fc receptors on phagocytes When IgG molecules, specific for a certain
antigen or surface component, bind to the pathogen with their Fab region, their Fc regions
point outwards, in direct reach of phagocytes.
Phagocytes bind those Fc regions with their Fc receptors.
Many low affinity interactions are formed between receptor and antibody that work together
to tightly bind the antibody-coated microbe.
The low individual affinity prevents Fc receptors from binding antibodies in the absence of
antigen, and therefore reduces the chance of immune cell activation in the absence of
infection.
This also prevents agglutination of phagocytes by antibody when there is no antigen.
After a pathogen has been bound, interactions between the Fc region of the antibody and
the Fc receptors of the phagocyte results in the initiation of phagocytosis.
The pathogen becomes engulfed by the phagocyte by an active process involving the binding
and releasing of the Fc region/Fc receptor complex, until the cell membrane of the phagocyte
completely encloses the pathogen.
Fc receptors on NK cells The Fc receptor on NK cells recognize IgG
that is bound to the surface of a pathogen-infected target cell and is called CD16 or FcγRIII.
Activation of FcγRIII by IgG causes the release of cytokines such as IFN-γ that signal to
other immune cells, and cytotoxic mediators like perforin and granzyme that enter the
target cell and promote cell death by triggering apoptosis.
This process is known as antibody-dependent cell-mediated cytotoxicity.
FcγRIII on NK cells can also associate with monomeric IgG.
When this occurs, the Fc receptor inhibits the activity of the NK cell.
Fc receptors on mast cells
IgE antibodies bind to antigens of allergens.
These allergen-bound IgE molecules interact with Fcε receptors on the surface of mast
cells.
Activation of mast cells following engagement of FcεRI results in a process called degranulation,
whereby the mast cell releases preformed molecules from its cytoplasmic granules; these are a
mixture of compounds including histamine, proteoglycans, and serine proteases.
Activated mast cells also synthesize and secrete lipid-derived mediators and cytokines (such
as interleukin 1, interleukin 3, interleukin 4, interleukin 5, interleukin 6, interleukin
13, tumor necrosis factor-alpha, GM-CSF, and several chemokines.
These mediators contribute to inflammation by attracting other leukocytes.
Fc receptors on eosinophils Large parasites like the helminth Schistosoma
mansoni are too large for ingestion by phagocytes.
They also have an external structure called an integument that is resistant to attack
by substances released by macrophages and mast cells.
However, these parasites can become coated with IgE and recognized by FcεRI on the surface
of eosinophils.
Activated eosinophils release preformed mediators such as major basic protein, and enzymes such
as peroxidase, against which helminths are not resistant.
The interaction of the FcεRI receptor with the Fc portion of helminth bound IgE causes
the eosinophil to release these molecules in a mechanism similar to that of the NK cell
during ADCC.
See also Fc receptor-like molecule
References
Further reading Immunobiology.
5th ed.
Janeway, Charles A.; Travers, Paul; Walport, Mark; Shlomchik, Mark.
New York and London: Garland Publishing; c2001.
Cellular and molecular immunology / Abul K. Abbas, Andrew H. Lichtman ; illustrations
by David L. Baker, Alexandra Baker.
Philadelphia, PA : Elsevier Saunders, c2005 Stimulatory and inhibitory signals originating
from the macrophage Fcγ receptors.
Jeffrey S. Gerber and David M. Mosser.
Microbes Infect. 2001 Feb;3(2):131-9.
External links Fc Receptor at the US National Library of
Medicine Medical Subject Headings