Fc receptor

Source: Wikipedia, the free encyclopedia.
Immunoglobulin-like receptor
Schematic diagram showing Fc receptor interaction with an antibody-coated microbial pathogen
Identifiers
SymbolFc receptor
Membranome10

In

B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, 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-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.[1]

Classes

There are several different types of Fc receptors (abbreviated FcR), which are classified based on the

IgE are called Fc-epsilon receptors (FcεR). The classes of FcR's are also distinguished by the cells that express them (macrophages, granulocytes, natural killer cells, T and B cells) and the signalling properties of each receptor.[2]

Fc-gamma receptors

All of the Fcγ receptors (FcγR) belong to the

immunoglobulin (Ig)-like domains, one more domain than FcγRII or FcγRIII has. This property allows FcγRI to bind a sole IgG molecule (or monomer), but all Fcγ receptors must bind multiple IgG molecules within an immune complex to be activated.[5]

The Fc-gamma receptors differ in their affinity for IgG and likewise the different IgG subclasses have unique affinities for each of the Fc gamma receptors.[6] These interactions are further tuned by the glycan (oligosaccharide) at position CH2-84.4 of IgG.[6] For example, by creating steric hindrance, fucose containing CH2-84.4 glycans reduce IgG affinity for FcγRIIIA.[6] In contrast, G0 glycans, which lack galactose and terminate instead with GlcNAc moieties, have increased affinity for FcγRIIIA.[6]

Neonatal Fc Receptor

Another FcR is expressed on multiple cell types and is similar in structure to

FcRn).[8][9]
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 (or CD89).

type I transmembrane protein. With one Ig-like domain in its extracellular portion, this Fc receptor is also a member of the immunoglobulin superfamily.[12]

Fc-epsilon receptors

Two types of FcεR are known:[3]

Summary table

Receptor name Principal antibody ligand Affinity for ligand Cell distribution Effect following binding to antibody
FcγRI (CD64) IgG1 and IgG3 High (Kd ~ 10−9 M)
Dendritic cells
Phagocytosis
Cell activation
Activation of respiratory burst
Induction of microbe killing
FcγRIIA (CD32) IgG Low (Kd > 10−7 M) Macrophages
Neutrophils
Eosinophils
Langerhans cells
Phagocytosis
Degranulation (eosinophils)
FcγRIIB1 (CD32) IgG Low (Kd > 10−7 M)
Mast cells
No phagocytosis
Inhibition of cell activity
FcγRIIB2 (CD32) IgG Low (Kd > 10−7 M) Macrophages
Neutrophils
Eosinophils
Phagocytosis
Inhibition of cell activity
FcγRIIIA (
CD16a
)
IgG Low (Kd > 10−6 M)
Macrophages
(certain tissues)
Induction of
antibody-dependent cell-mediated cytotoxicity
(ADCC)
Induction of cytokine release by macrophages
FcγRIIIB (
CD16b
)
IgG Low (Kd > 10−6 M) Eosinophils
Macrophages
Neutrophils
Mast cells
Follicular dendritic cells
Induction of microbe killing
FcεRI
IgE High (Kd ~ 10−10 M) Mast cells
Eosinophils
Basophils
Langerhans cells
Monocytes
Degranulation
Phagocytosis
FcεRII (CD23) IgE Low (Kd > 10−7 M) B cells
Eosinophils
Langerhans cells
Possible adhesion molecule
IgE transport across human intestinal epithelium
Positive-feedback mechanism to enhance allergic sensitization (B cells)
FcαRI (
CD89
)
IgA Low (Kd > 10−6 M) Monocytes
Macrophages
Neutrophils
Eosinophils
Phagocytosis
Induction of microbe killing
Fcα/μR (CD351) IgA and IgM High for IgM, Mid for IgA B cells
Mesangial cells
Macrophages
Endocytosis
Induction of microbe killing
FcμR[17] IgM (unknown) Human FcμR is predominantly expressed by lymphocytes, but not by phagocytes [18] function has not been fully elucidated / diverse [19]
FcRn
IgG high in acidic cellular endosomes
low in pH neutral extracellular environment
Monocytes
Macrophages
Endothelial cells
Hepatocytes

Transfers IgG from a mother to fetus through the placenta
Transfers IgG from a mother to infant in milk
Protects IgG from degradation
Transfers IgG across endothelial/epithelial layers

Functions

An antibody has Fab (fragment, antigen-binding) and Fc (fragment, crystallizable) regions. Fc receptors bind to the Fc region.

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 (natural killer cells) or adaptive immune system (e.g., B cells).[20][21][22] 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

antibody-dependent cell-mediated cytotoxicity (ADCC). During ADCC, FcγRIII receptors on the surface of natural killer (NK) cells stimulate the NK cells to release cytotoxic molecules from their granules to kill antibody-covered target cells.[25]
FcεRI has a different function. FcεRI is the Fc receptor on
IgE molecules and their Fc receptors on the surface of a granulocyte will trigger the cell to rapidly release preformed mediators from its granules.[3]

Signaling mechanisms - Fc gamma receptors

Activation

Fc gamma receptors belong to the group of

intracellular tail of a receptor. When phosphate groups are added to the tyrosine (Y) residue of the ITAM by membrane-anchored enzymes of the Src kinase family, 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.

Inhibition

The presence of only one YXXL motif is not sufficient to activate cells, and represents a motif (I/VXXYXXL) known as an

SHP-1 and SHIP-1 inhibit signaling by Fcγ receptors.[28] 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 (e.g. c-Kit).[29]

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.:

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+.[31]

Cellular activation

opsonized
microbe.

On phagocytes

When

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.[32]

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.

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 (ADCC). FcγRIII on NK cells can also associate with monomeric IgG (i.e., IgG that is not antigen-bound). When this occurs, the Fc receptor inhibits the activity of the NK cell.[34]

On mast cells

Activation of mast cell degranulation by IgE interaction with FcεRI. 1 = antigen; 2 = IgE; 3 = FcεRI; 4 = preformed mediators (histamine, proteases, chemokines, heparin); 5 = granules; 6 – mast cell; 7 – newly formed mediators (prostaglandins, leukotrienes, thromboxanes, platelet-activating factor)

leukocytes
.

On eosinophils

Large parasites like the

FcεRII 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.[40]

On T lymphocytes

CD4+ T cells (mature Th cells) provide help to B cells that produce antibodies. Several subsets of activated effector CD4+ T cells are observed in disease pathology. Earlier studies summarized by Sanders and Lynch in 1993 suggested critical roles for FcRs in CD4+ T cell mediated immune responses and proposed the formation of a joint signaling complex among FcRs and TCR on the cell surface.[41][42][43][44] Chauhan and coworkers reported the colocalization of the labeled ICs with the CD3 complex on activated CD4+ T cell surface, which thus suggest the coexistence of FcRs together with TCR complex.[45] Both of these receptors are observed forming an apical structure on the membrane of activated CD4+ T cells, suggesting the lateral movement of these receptors.[46] Co-migration of FcRs with TCR and BCR complex is observed on the cells surface and T:B cell cytoconjugates show this coexistence at the point of contact.[47] An earlier review suggested that the expression of FcRs on CD4+ T cells is an open question.[48] This established the current paradigm that T cells do not express FcRs and these findings were never challenged and experimentally tested.[49] Chauhan and coworkers showed binding of immune complexes (ICs), the FcR ligand to activated CD4+ T cells.[49] CD16a expression is induced in the activated human naïve CD4+ T cells, which express CD25, CD69, and CD98 and ligation to ICs leads to generation of effector memory cells.[50] CD16a signaling is mediated by phosphorylation of Syk (pSyk).[50][51][52]

A study now suggests induced expression of CD32a upon activation of human CD4+ T cells, similar to CD16a.[51][53] CD32a expression on CD4+ T cells was also suggested by three independent studies from HIV-1 researchers. The expression of CD16a and CD32a in a subset of activated CD4+ T cells is now confirmed.[51][53] FcRs on the cell surface upon binding to ICs composed of nucleic acids trigger cytokine production and upregulate nucleic acid sensing pathways. FcRs are present both on the cell surface and in the cytosol. CD16a signaling upregulate the expression of nucleic acid sensing toll-like receptors and relocate them to cell surface.[50][54] CD16a is a new costimulatory signal for human CD4+ T cells, which successfully substitute the CD28 requirement during autoimmunity.[55] In an autoimmune background CD4+ T cells bypass the requirement of CD28 cosignaling to become fully activated.[55] Furthermore, the blockade of CD28 cosignaling does not inhibit the development of TFH cells, a key subset for the generation of autoantibody producing autoreactive plasma B cells.[56] A balance among costimulatory and inhibitory signals is required for immune homeostasis. Excessive costimulation and/or insufficient co-inhibition leads to the tolerance-breakdown and autoimmunity. CD16a mediated costimulation provides a positive signal in the activated CD4+ T cells and not in the quiescent cells which lack FcγR expression.[51]

See also

References

Further reading

External links