Fc receptor

There are several different types of Fc receptors (abbreviated FcR), 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 (FcγR), those that bind IgA are called Fc-alpha receptors (FcαR) and those that bind IgE are called Fc-epsilon receptors (FcεR). The classes of FcRs 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.{{cite book|last1=Owen|first1=Judith|title=Immunology|last2=Punt|first2=Jenni|last3=Stranford|first3=Sharon|last4=Jones|first4=Patricia|date=2009|publisher=W.H. Freeman and Company|isbn=978-14641-3784-6|edition=7th|location=New York|page=423|name-list-style=vanc}}

All of the Fcγ receptors (FcγR) belong to the immunoglobulin superfamily and are the most important Fc receptors for inducing phagocytosis of opsonized (marked) microbes.{{cite journal | vauthors = Fridman WH | title = Fc receptors and immunoglobulin binding factors | journal = FASEB Journal | volume = 5 | issue = 12 | pages = 2684–90 | date = September 1991 | pmid = 1916092 | doi = 10.1096/fasebj.5.12.1916092 | doi-access = free | s2cid = 16805557 }} This family includes several members, FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b), which differ in their antibody affinities due to their different molecular structure.{{cite journal | vauthors = Indik ZK, Park JG, Hunter S, Schreiber AD | title = The molecular dissection of Fc gamma receptor mediated phagocytosis | journal = Blood | volume = 86 | issue = 12 | pages = 4389–99 | date = December 1995 | pmid = 8541526 | doi = 10.1182/blood.V86.12.4389.bloodjournal86124389 | doi-access = free }} For instance, FcγRI binds to IgG more strongly than FcγRII or FcγRIII does. FcγRI also has an extracellular portion composed of three 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.{{cite journal | vauthors = Harrison PT, Davis W, Norman JC, Hockaday AR, Allen JM | title = Binding of monomeric immunoglobulin G triggers Fc gamma RI-mediated endocytosis | journal = The Journal of Biological Chemistry | volume = 269 | issue = 39 | pages = 24396–402 | date = September 1994 | doi = 10.1016/S0021-9258(19)51097-3 | pmid = 7929100 | doi-access = free }}

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. These interactions are further tuned by the glycan (oligosaccharide) at position CH2-84.4 of IgG. For example, by creating steric hindrance, fucose containing CH2-84.4 glycans reduce IgG affinity for FcγRIIIA. In contrast, G0 glycans, which lack galactose and terminate instead with GlcNAc moieties, have increased affinity for FcγRIIIA.

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.{{cite journal | vauthors = Zhu X, Meng G, Dickinson BL, Li X, Mizoguchi E, Miao L, Wang Y, Robert C, Wu B, Smith PD, Lencer WI, Blumberg RS | title = MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells | journal = Journal of Immunology | volume = 166 | issue = 5 | pages = 3266–76 | date = March 2001 | pmid = 11207281 | pmc = 2827247 | doi = 10.4049/jimmunol.166.5.3266 }} 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 (FcRn).{{cite journal | vauthors = Firan M, Bawdon R, Radu C, Ober RJ, Eaken D, Antohe F, Ghetie V, Ward ES | title = The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans | journal = International Immunology | volume = 13 | issue = 8 | pages = 993–1002 | date = August 2001 | pmid = 11470769 | doi = 10.1093/intimm/13.8.993 | doi-access = free }}{{cite journal | vauthors = Simister NE, Jacobowitz Israel E, Ahouse JC, Story CM | title = New functions of the MHC class I-related Fc receptor, FcRn | journal = Biochemical Society Transactions | volume = 25 | issue = 2 | pages = 481–6 | date = May 1997 | pmid = 9191140 | doi = 10.1042/bst0250481 }} Recently, research suggested that this receptor plays a role in the homeostasis of IgG serum levels.

Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89).{{cite journal | vauthors = Otten MA, van Egmond M | title = The Fc receptor for IgA (FcalphaRI, CD89) | journal = Immunology Letters | volume = 92 | issue = 1–2 | pages = 23–31 | date = March 2004 | pmid = 15081523 | doi = 10.1016/j.imlet.2003.11.018 }} FcαRI is found on the surface of neutrophils, eosinophils, monocytes, some macrophages (including Kupffer cells), 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 (MIRR) 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.{{cite journal | vauthors = Shibuya A, Honda S | title = Molecular and functional characteristics of the Fcalpha/muR, a novel Fc receptor for IgM and IgA | journal = Springer Seminars in Immunopathology | volume = 28 | issue = 4 | pages = 377–82 | date = December 2006 | pmid = 17061088 | doi = 10.1007/s00281-006-0050-3 | s2cid = 23794895 }} This receptor is called the Fc-alpha/mu receptor (Fcα/μR) 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.{{cite journal | vauthors = Cho Y, Usui K, Honda S, Tahara-Hanaoka S, Shibuya K, Shibuya A | title = Molecular characteristics of IgA and IgM Fc binding to the Fcalpha/muR | journal = Biochemical and Biophysical Research Communications | volume = 345 | issue = 1 | pages = 474–8 | date = June 2006 | pmid = 16681999 | doi = 10.1016/j.bbrc.2006.04.084 | url = https://tsukuba.repo.nii.ac.jp/?action=repository_action_common_download&item_id=17550&item_no=1&attribute_id=17&file_no=1 | hdl = 2241/102010 | hdl-access = free }}

Two types of FcεR are known:

• the high-affinity receptor FcεRI is a member of the immunoglobulin superfamily (it has two Ig-like domains). FcεRI is found on epidermal Langerhans cells, eosinophils, mast cells and basophils.{{cite journal | vauthors = Ochiai K, Wang B, Rieger A, Kilgus O, Maurer D, Födinger D, Kinet JP, Stingl G, Tomioka H | title = A review on Fc epsilon RI on human epidermal Langerhans cells | journal = International Archives of Allergy and Immunology | volume = 104 Suppl 1 | issue = 1 | pages = 63–4 | year = 1994 | pmid = 8156009 | doi = 10.1159/000236756 }}{{cite journal | vauthors = Prussin C, Metcalfe DD | title = 5. IgE, mast cells, basophils, and eosinophils | journal = The Journal of Allergy and Clinical Immunology | volume = 117 | issue = 2 Suppl Mini–Primer | pages = S450-6 | date = February 2006 | pmid = 16455345 | doi = 10.1016/j.jaci.2005.11.016 }} 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.{{cite journal | vauthors = von Bubnoff D, Novak N, Kraft S, Bieber T | title = The central role of FcepsilonRI in allergy | journal = Clinical and Experimental Dermatology | volume = 28 | issue = 2 | pages = 184–7 | date = March 2003 | pmid = 12653710 | doi = 10.1046/j.1365-2230.2003.01209.x | s2cid = 2080598 }}
• the low-affinity receptor FcεRII (CD23) 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.{{cite book | vauthors = Kikutani H, Yokota A, Uchibayashi N, Yukawa K, Tanaka T, Sugiyama K, Barsumian EL, Suemura M, Kishimoto T | title = Ciba Foundation Symposium 147 - IgE, Mast Cells and the Allergic Response | chapter = Structure and Function of Fc _ε Receptor II (Fc _ε RII/CD23): A Point of Contact Between the Effector Phase of Allergy and B Cell Differentiation | series = Novartis Foundation Symposia | date = 2007 | volume = 147 | pages = 23–35 | pmid = 2695308 | doi = 10.1002/9780470513866.ch3 | isbn = 9780470513866 }}

File:2fab fc.svg (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).{{cite journal | vauthors = Selvaraj P, Fifadara N, Nagarajan S, Cimino A, Wang G | title = Functional regulation of human neutrophil Fc gamma receptors | journal = Immunologic Research | volume = 29 | issue = 1–3 | pages = 219–30 | year = 2004 | pmid = 15181284 | doi = 10.1385/IR:29:1-3:219 | s2cid = 85351071 }}{{cite journal | vauthors = Sulica A, Chambers WH, Manciulea M, Metes D, Corey S, Rabinowich H, Whiteside TL, Herberman RB | title = Divergent signal transduction pathways and effects on natural killer cell functions induced by interaction of Fc receptors with physiologic ligands or antireceptor antibodies | journal = Natural Immunity | volume = 14 | issue = 3 | pages = 123–33 | year = 1995 | pmid = 8832896 }}{{cite journal | vauthors = Sarfati M, Fournier S, Wu CY, Delespesse G | title = Expression, regulation and function of human Fc epsilon RII (CD23) antigen | journal = Immunologic Research | volume = 11 | issue = 3–4 | pages = 260–72 | year = 1992 | pmid = 1287120 | doi = 10.1007/BF02919132 | s2cid = 83698996 }}

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 (or tail), an interaction that activates the cell that possesses the Fc receptor.{{cite journal | vauthors = Raghavan M, Bjorkman PJ | title = Fc receptors and their interactions with immunoglobulins | journal = Annual Review of Cell and Developmental Biology | volume = 12 | pages = 181–220 | year = 1996 | pmid = 8970726 | doi = 10.1146/annurev.cellbio.12.1.181 | url = https://authors.library.caltech.edu/980/1/BJOarcdb96.pdf }} 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.{{cite journal | vauthors = Swanson JA, Hoppe AD | title = The coordination of signaling during Fc receptor-mediated phagocytosis | journal = Journal of Leukocyte Biology | volume = 76 | issue = 6 | pages = 1093–103 | date = December 2004 | pmid = 15466916 | doi = 10.1189/jlb.0804439 | hdl = 2027.42/141562 | s2cid = 13912335 | hdl-access = free }} Another process involving Fc receptors is called 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.{{cite journal | vauthors = Sun PD | title = Structure and function of natural-killer-cell receptors | journal = Immunologic Research | volume = 27 | issue = 2–3 | pages = 539–48 | year = 2003 | pmid = 12857997 | doi = 10.1385/IR:27:2-3:539 | s2cid = 29921323 | url = https://zenodo.org/record/1236303 }}

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 at least two IgE molecules and their Fc receptors on the surface of a granulocyte will trigger the cell to rapidly release preformed mediators from its granules.

Fc gamma receptors belong to the group of non-catalytic tyrosine-phosphorylated receptors which share a similar signalling pathway involving phosphorylation of tyrosine residues.{{cite journal| vauthors = Dushek O, Goyette J, van der Merwe PA| title = Non-catalytic tyrosine- phosphorylated receptors | journal = Immunological Reviews| volume = 250 | issue = 1| pages = 258–276 | date = November 2012| pmid = 23046135| doi = 10.1111/imr.12008 | s2cid = 1549902 }} The receptors generate signals within their cells through an important activation motif known as an immunoreceptor tyrosine-based activation motif (ITAM).{{cite journal | vauthors = Cambier JC | title = New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL) | journal = Immunology Today | volume = 16 | issue = 2 | pages = 110 | date = February 1995 | pmid = 7888063 | doi = 10.1016/0167-5699(95)80105-7 }} An ITAM is a specific sequence of amino acids (YXXL) occurring twice in close succession in the 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.

The presence of only one YXXL motif is not sufficient to activate cells, and represents a motif (I/VXXYXXL) known as an immunoreceptor tyrosine-based inhibitory motif (ITIM). 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.{{cite journal | vauthors = Huang ZY, Hunter S, Kim MK, Indik ZK, Schreiber AD | title = The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fcgamma receptors FcgammaRIIB and FcgammaRIIA | journal = Journal of Leukocyte Biology | volume = 73 | issue = 6 | pages = 823–9 | date = June 2003 | pmid = 12773515 | doi = 10.1189/jlb.0902454 | s2cid = 14502303 | doi-access = free }} 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).{{cite journal | vauthors = Cambier JC | title = Inhibitory receptors abound? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 12 | pages = 5993–5 | date = June 1997 | pmid = 9177155 | pmc = 33673 | doi = 10.1073/pnas.94.12.5993 | bibcode = 1997PNAS...94.5993C | doi-access = free }}

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.:{{cite journal | vauthors = Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV | title = Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice | journal = Nature | volume = 379 | issue = 6563 | pages = 346–9 | date = January 1996 | pmid = 8552190 | doi = 10.1038/379346a0 | bibcode = 1996Natur.379..346T | s2cid = 4364705 }} Experiments using B cell deletion mutants and dominant-negative enzymes have firmly established an important role for SH2-domain-containing inositol 5-phosphatase (SHIP) 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+.{{cite journal | vauthors = Coggeshall KM | title = Inhibitory signaling by B cell Fc gamma RIIb | journal = Current Opinion in Immunology | volume = 10 | issue = 3 | pages = 306–12 | date = June 1998 | pmid = 9638367 | doi = 10.1016/s0952-7915(98)80169-6 }}

Image:Fc receptor response.pngs that have been bound by antibodies. The interaction between the bound antibodies and the cell surface Fc receptor activates the immune cell to kill the microbe. This example shows the phagocytosis of an opsonized microbe.]]

When IgG molecules, specific for a certain antigen or surface component, bind to the pathogen with their Fab region (fragment antigen binding 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 (clotting) 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.{{cite journal | vauthors = Joshi T, Butchar JP, Tridandapani S | title = Fcgamma receptor signaling in phagocytes | journal = International Journal of Hematology | volume = 84 | issue = 3 | pages = 210–6 | date = October 2006 | pmid = 17050193 | doi = 10.1532/IJH97.06140 | s2cid = 6501210 }}

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.{{cite journal | vauthors = Trinchieri G, Valiante N | title = Receptors for the Fc fragment of IgG on natural killer cells | journal = Natural Immunity | volume = 12 | issue = 4–5 | pages = 218–34 | year = 1993 | pmid = 8257828 }} 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 (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.{{cite journal | vauthors = Sulica A, Galatiuc C, Manciulea M, Bancu AC, DeLeo A, Whiteside TL, Herberman RB | title = Regulation of human natural cytotoxicity by IgG. IV. Association between binding of monomeric IgG to the Fc receptors on large granular lymphocytes and inhibition of natural killer (NK) cell activity | journal = Cellular Immunology | volume = 147 | issue = 2 | pages = 397–410 | date = April 1993 | pmid = 8453679 | doi = 10.1006/cimm.1993.1079 }}

Image:Allergy degranulation processes 01.svg

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.{{cite journal | vauthors = Yamasaki S, Saito T | title = Regulation of mast cell activation through FcepsilonRI | journal = Chemical Immunology and Allergy | volume = 87 | pages = 22–31 | year = 2005 | pmid = 16107760 | doi = 10.1159/000087568 | isbn = 3-8055-7948-9 }} Activated mast cells also synthesize and secrete lipid-derived mediators (such as prostaglandins, leukotrienes, and platelet-activating factor) 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.{{cite journal | vauthors = Wakahara S, Fujii Y, Nakao T, Tsuritani K, Hara T, Saito H, Ra C | title = Gene expression profiles for Fc epsilon RI, cytokines and chemokines upon Fc epsilon RI activation in human cultured mast cells derived from peripheral blood | journal = Cytokine | volume = 16 | issue = 4 | pages = 143–52 | date = November 2001 | pmid = 11792124 | doi = 10.1006/cyto.2001.0958 }}{{cite journal | vauthors = Metcalfe DD, Baram D, Mekori YA | title = Mast cells | journal = Physiological Reviews | volume = 77 | issue = 4 | pages = 1033–79 | date = October 1997 | pmid = 9354811 | doi = 10.1152/physrev.1997.77.4.1033 }} These mediators contribute to inflammation by attracting other leukocytes.

Large parasites like the helminth (worm) 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 FcεRII 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.{{cite journal | vauthors = David JR, Butterworth AE, Vadas MA | title = Mechanism of the interaction mediating killing of Schistosoma mansoni by human eosinophils | journal = The American Journal of Tropical Medicine and Hygiene | volume = 29 | issue = 5 | pages = 842–8 | date = September 1980 | pmid = 7435788 | doi = 10.4269/ajtmh.1980.29.842 }}{{cite journal | vauthors = Capron M, Soussi Gounni A, Morita M, Truong MJ, Prin L, Kinet JP, Capron A | title = Eosinophils: from low- to high-affinity immunoglobulin E receptors | journal = Allergy | volume = 50 | issue = 25 Suppl | pages = 20–3 | year = 1995 | pmid = 7677229 | doi = 10.1111/j.1398-9995.1995.tb04270.x | s2cid = 36197719 | url = https://zenodo.org/record/1230625 }} The interaction of 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.{{cite journal | vauthors = Gounni AS, Lamkhioued B, Ochiai K, Tanaka Y, Delaporte E, Capron A, Kinet JP, Capron M | title = High-affinity IgE receptor on eosinophils is involved in defence against parasites | journal = Nature | volume = 367 | issue = 6459 | pages = 183–6 | date = January 1994 | pmid = 8114916 | doi = 10.1038/367183a0 | bibcode = 1994Natur.367..183S | s2cid = 4331405 }}

CD4+ T cells (mature T_h 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.{{cite journal | vauthors = Pichler WJ, Lum L, Broder S | year = 1978 | title = Fc-receptors on human T lymphocytes. I. Transition of Tgamma to Tmu cells | journal = J Immunol | volume = 121 | issue = 4| pages = 1540–1548 | doi = 10.4049/jimmunol.121.4.1540 | pmid = 308968 }}{{cite journal | vauthors = Sandor M, Lynch RG | title = Lymphocyte Fc receptors: the special case of T cells | journal = Immunol. Today | volume = 14 | issue = 5 | pages = 227–31 | date = May 1993 | pmid = 8517922 | doi = 10.1016/0167-5699(93)90168-K }}{{cite journal | vauthors = Engelhardt W, Matzke J, Schmidt RE | year = 1995 | title = Activation-dependent expression of low affinity IgG receptors Fc gamma RII(CD32) and Fc gamma RIII(CD16) in subpopulations of human T lymphocytes | journal = Immunobiology | volume = 192 | issue = 5| pages = 297–320 | doi=10.1016/s0171-2985(11)80172-5| pmid = 7649565 }}{{cite journal | vauthors = Moretta L, Webb SR, Grossi CE, Lydyard PM, Cooper MD | year = 1977 | title = Functional analysis of two human T-cell subpopulations: help and suppression of B-cell responses by T cells bearing receptors for IgM or IgG | journal = J Exp Med | volume = 146 | issue = 1| pages = 184–200 | doi=10.1084/jem.146.1.184| pmid = 301544 | pmc = 2180738 }} 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.{{cite journal | author = Chauhan AK, Moore TL | year = 2011 | title = T cell activation by terminal complex of complement and immune complexes | journal = The Journal of Biological Chemistry | volume = 286 | issue = 44| pages = 38627–38637 | doi = 10.1074/jbc.M111.266809 | pmid = 21900254 | pmc = 3207419 | doi-access = free }} 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.{{cite journal | author = Chauhan AK, Moore TL | year = 2011 | title = T cell activation by terminal complex of complement and immune complexes | journal = The Journal of Biological Chemistry | volume = 286 | issue = 44| pages = 38627–38637 | doi = 10.1074/jbc.M111.266809 | pmid = 21900254 | pmc = 3207419 | doi-access = free }} 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.{{cite journal | author = Sandor M, Lynch RG | year = 1993 | title = Lymphocyte Fc receptors: the special case of T cells | journal = Immunology Today | volume = 14 | issue = 5| pages = 227–231 | doi = 10.1016/0167-5699(93)90168-K | pmid = 8517922 }} An earlier review suggested that the expression of FcRs on CD4+ T cells is an open question.{{cite journal | vauthors = Nimmerjahn F, Ravetch JV | title = Fcgamma receptors as regulators of immune responses | journal = Nat. Rev. Immunol. | volume = 8 | issue = 1 | pages = 34–47 | date = January 2008 | pmid = 18064051 | doi = 10.1038/nri2206 | s2cid = 34597359 }} This established the current paradigm that T cells do not express FcRs and these findings were never challenged and experimentally tested.{{cite journal | vauthors = Bruhns P, Jönsson F | title = Mouse and human FcR effector functions | journal = Immunol. Rev. | volume = 268 | issue = 1 | pages = 25–51 | date = November 2015 | pmid = 26497511 | doi = 10.1111/imr.12350 | s2cid = 19544801 }} Chauhan and coworkers showed binding of immune complexes (ICs), the FcR ligand to activated CD4+ T cells. 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.{{cite journal | vauthors = Chauhan AK, Moore TL, Bi Y, Chen C | title = FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression | journal = J. Biol. Chem. | volume = 291 | issue = 3 | pages = 1368–86 | date = January 2016 | pmid = 26582197 | pmc = 4714221 | doi = 10.1074/jbc.M115.684795 | doi-access = free }} CD16a signaling is mediated by phosphorylation of Syk (pSyk).{{cite journal | vauthors = Chauhan AK, Chen C, Moore TL, DiPaolo RJ | title = Induced expression of FcγRIIIa (CD16a) on CD4+ T cells triggers generation of IFN-γhigh subset | journal = J. Biol. Chem. | volume = 290 | issue = 8 | pages = 5127–40 | date = February 2015 | pmid = 25556651 | pmc = 4335247 | doi = 10.1074/jbc.M114.599266 | doi-access = free }}{{cite journal | author = Chauhan AK, Moore TL | year = 2012 | title = Immune complexes and late complement proteins trigger activation of Syk tyrosine kinase in human CD4(+) T cells | journal = Clin Exp Immunol | volume = 167 | issue = 2| pages = 235–245 | doi = 10.1111/j.1365-2249.2011.04505.x | pmid = 22235999 | pmc = 3278689 }}

A study now suggests induced expression of CD32a upon activation of human CD4+ T cells, similar to CD16a.{{cite journal | vauthors = Holgado MP, Sananez I, Raiden S, Geffner JR, Arruvito L | title = CD32 Ligation Promotes the Activation of CD4+ T Cells | journal = Front Immunol | volume = 9 | pages = 2814 | date = 2018 | pmid = 30555482 | pmc = 6284025 | doi = 10.3389/fimmu.2018.02814 | doi-access = free }} 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. 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.{{cite journal | author = Chauhan AK | year = 2017 | title = FcgammaRIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells | journal = J Immunol | volume = 198 | issue = 12| pages = 4596–4606 | doi = 10.4049/jimmunol.1601954 | pmid = 28500073 | pmc = 5505339 }} CD16a is a new costimulatory signal for human CD4+ T cells, which successfully substitute the CD28 requirement during autoimmunity.{{cite journal | vauthors = Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA | year = 2011 | title = Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family | journal = Immunol Rev | volume = 241 | issue = 1| pages = 180–205 | doi = 10.1111/j.1600-065X.2011.01011.x | pmid = 21488898 | pmc = 3077803 }} In an autoimmune background CD4+ T cells bypass the requirement of CD28 cosignaling to become fully activated. 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.{{cite journal | vauthors = Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, Gentz LJ, Vu Van D, Mages HW, Haftmann C, Riedel R, Grun JR, Schuh W, Kroczek RA, Radbruch A, Mashreghi MF, Hutloff A | year = 2015 | title = ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2 | journal = The Journal of Experimental Medicine | volume = 212 | issue = 2| pages = 217–233 | doi = 10.1084/jem.20141432 | pmid = 25646266 | pmc = 4322049 }} 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.

• Fc receptor-like molecule

{{reflist|33em|refs=

{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | issue = 6 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}

}}

{{refbegin|33em}}

• {{cite book | last1 = Janeway | first1 = Charles A. | first2 = Paul | last2 = Travers | first3 = Mark | last3 = Waldport | first4 = Mark J | last4 = Shlomchik | name-list-style = vanc | title = Immunobiology: The Immune System in Health and Disease | date = 2001 | publisher = Garland | location = New York | isbn = 978-0-8153-3642-6 | edition = 5th | chapter = Chapter 9. The Humoral Immune Response | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK27171/#A1236 | url-access = registration | url = https://archive.org/details/immunobiology00char }}
• {{cite book | last1 = Abbas | first1 = Abul K. | last2 = Lichtman | first2 = Andrew H. | last3 = Pillai | first3 = Shiv | name-list-style = vanc | title = Cellular and molecular immunology | date = 2012 | publisher = Elsevier/Saunders | location = Philadelphia | isbn = 978-1-4377-1528-6 | edition = 7th | chapter = Chapter 12: Effector Mechanisms of Humoral Immunity }}
• {{cite journal | vauthors = Gerber JS, Mosser DM | title = Stimulatory and inhibitory signals originating from the macrophage Fcgamma receptors | journal = Microbes and Infection | volume = 3 | issue = 2 | pages = 131–9 | date = February 2001 | pmid = 11251299 | doi = 10.1016/s1286-4579(00)01360-5 }}
• {{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}

{{refend}}

• {{MeshName|Fc+Receptor}}

{{Immune receptors}}

{{DEFAULTSORT:Fc Receptor}}

Category:Cell signaling