View source for T-cell receptor

{{Infobox protein family
| Symbol = TCR_zetazeta
| Name = 
| image = TCRComplex.png
| width = 
| caption = The '''T-cell receptor complex''' with TCR-α and TCR-β chains, [[CD3 receptor|CD3]] and ζ-chain accessory molecules.
| Pfam = PF11628
| Pfam_clan =  
| InterPro = IPR021663
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 166
| OPM protein = 2hac
| CAZy = 
| CDD = 
| Membranome superfamily = 26
}}
[[File:Antigen presentation.svg|thumb|300px|Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.]]
{{Infobox protein
| Name = T-cell receptor alpha locus
| caption =
| image =
| width =
| HGNCid = 12027
| Symbol = [[TRA (gene)|TRA]]
| AltSymbols = TCRA, TRA@
| EntrezGene = 6955
| OMIM = 186880
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 11.2
| LocusSupplementaryData =
}}
{{Infobox protein
| Name = T-cell receptor beta locus
| caption =
| image =
| width =
| HGNCid = 12155
| Symbol = TRB
| AltSymbols = TCRB, TRB@
| EntrezGene = 6957
| OMIM = 186930
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 7
| Arm = q
| Band = 34
| LocusSupplementaryData =
}}
{{Infobox protein
| Name = T-cell receptor delta locus
| caption =
| image =
| width =
| HGNCid = 12252
| Symbol = [[TRD (gene)|TRD]]
| AltSymbols = TCRD, TRD@, TCRDV1
| EntrezGene = 6964
| OMIM = 
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 11.2
| LocusSupplementaryData =
}}
{{Infobox protein
| Name = T-cell receptor gamma locus
| caption =
| image =
| width =
| HGNCid = 12271
| Symbol = [[TRG (gene)|TRG]]
| AltSymbols = TCRG, TRG@
| EntrezGene = 6965
| OMIM = 
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 7
| Arm = p
| Band = 14
| LocusSupplementaryData =
}}

The '''T-cell receptor''', or '''TCR''', is a molecule found on the surface of [[T cell]]s, or T lymphocytes,<ref name="KindtGoldsby2007">{{cite book|author1=Thomas J. Kindt|author2=Richard A. Goldsby|author3=Barbara Anne Osborne|author4=Janis Kuby|title=Kuby immunology|url=https://books.google.com/books?id=oOsFf2WfE5wC&pg=PA223|access-date=28 November 2010|year=2007|publisher=Macmillan|isbn=978-1-4292-0211-4|pages=223–}}</ref> that is responsible for recognizing fragments of [[antigen]] as peptides bound to [[major histocompatibility complex]] (MHC) molecules. The binding between TCR and antigen peptides is of relatively low [[Affinity (pharmacology)#Protein-ligand binding|affinity]] and is [[degeneracy (biology)|degenerate]]: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.<ref name="pmid_22918468">{{Citation |last=Sewell |first=AK |year=2012 |title=Why must T cells be cross-reactive |journal=Nat Rev Immunol |volume=12 |issue=9|pages=669–677 |pmid=22918468 |doi=10.1038/nri3279}}</ref>

The TCR is composed of two different protein chains (that is, it is a [[heteromer|hetero]][[protein dimer|dimer]]). In humans, in 95% of T cells the TCR consists of an alpha (α) chain and a beta (β) chain (encoded by ''[[TRA (gene)|TRA]]'' and ''TRB'', respectively), whereas in 5% of T cells the TCR consists of [[gamma/delta T cells|gamma and delta]] (γ/δ) chains (encoded by ''[[TRG (gene)|TRG]]'' and ''[[TRG (gene)|TRD]]'', respectively). This ratio changes during [[ontogeny]] and in diseased states (such as [[leukemia]]). It also differs between species. [[Homology (biology)|Orthologues]] of the 4 [[locus (genetics)|loci]] have been mapped in various species.<ref name="pmid_11567625">{{cite journal | vauthors = Glusman G, Rowen L, Lee I, Boysen C, Roach JC, Smit AF, Wang K, Koop BF, Hood L | title = Comparative genomics of the human and mouse T cell receptor loci | journal = Immunity | volume = 15 | issue = 3 | pages = 337–49 | date = September 2001 | pmid = 11567625 | pmc =  | doi = 10.1016/s1074-7613(01)00200-x | postscript = . }}</ref><ref name="pmid_16484802">{{cite journal | vauthors = Deakin JE, Parra ZE, Graves JA, Miller RD | title = Physical mapping of T cell receptor loci (TRA@, TRB@, TRD@ and TRG@) in the opossum (Monodelphis domestica) | journal = Cytogenetic and Genome Research | volume = 112 | issue = 3-4 | pages = 342K | year = 2006 | pmid = 16484802 | pmc =  | doi = 10.1159/000089901 | postscript = . }}</ref> Each locus can produce a variety of [[peptide|polypeptides]] with constant and variable regions.<ref name="pmid_11567625"/>

When the TCR engages with antigenic peptide and MHC (peptide/MHC), the T lymphocyte is activated through signal transduction, that is, a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors.

== History of the TCR ==
In 1984, [[Tak Wah Mak]]<ref>{{cite journal | vauthors = Yanagi Y, Yoshikai Y, Leggett K, Clark SP, Aleksander I, Mak TW | title = A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains | journal = Nature | volume = 308 | issue = 5955 | pages = 145–9 | date = 1984-03-08 | pmid = 6336315 | doi = 10.1038/308145a0 }}</ref> and [[Mark M. Davis]]<ref>{{cite journal | vauthors = Hedrick SM, Cohen DI, Nielsen EA, Davis MM | title = Isolation of cDNA clones encoding T cell-specific membrane-associated proteins | journal = Nature | volume = 308 | issue = 5955 | pages = 149–53 | date = 1984-03-08 | pmid = 6199676 | doi = 10.1038/308149a0 }}</ref> discovered the human and mouse TCR respectively. These findings allowed the entity and structure of the elusive TCR, known before as the "Holy Grail of Immunology", to be revealed. This allowed scientists from around the world to carry out studies on the TCR, leading to important studies in the fields of [[CAR-T]], [[Cancer immunotherapy]] and [[Checkpoint inhibition]].

==Structural characteristics of the TCR==
The TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (α) and beta (β) chains expressed as part of a complex with the invariant [[CD3 (immunology)|CD3]] chain molecules.  T cells expressing this receptor are referred to as α:β (or αβ) T cells, though a minority of T cells express an alternate receptor, formed by variable gamma (γ) and delta (δ) chains, referred as γδ T cells.<ref name="Janeway Immunobiology - Glossary">{{cite book|author1=Janeway CA Jr |author2=Travers P |author3=Walport M |title=Immunobiology: The Immune System in Health and Disease. 5th edition|year=2001|publisher=Garland Science|location=Glossary|url=https://www.ncbi.nlm.nih.gov/books/NBK10759/def-item/A3289/?report=objectonly|display-authors=etal}}</ref>

Each chain is composed of two extracellular domains: Variable (V) region and a Constant (C) region, both of [[Immunoglobulin superfamily]] (IgSF) [[Immunoglobulin domain|domain]] forming antiparallel [[Beta sheet|β-sheets]]. The Constant region is proximal to the cell membrane, followed by a transmembrane region and a short cytoplasmic tail, while the Variable region binds to the peptide/MHC complex.

The variable domain of both the TCR α-chain and β-chain each have three hypervariable or [[complementarity determining region]]s (CDRs). There is also an additional area of hypervariability on the β-chain (HV4) that does not normally contact antigen and, therefore, is not considered a CDR.

The residues in these variable domains are located in two regions of the TCR, at the interface of the α- and β-chains and in the β-chain [[framework region]] that is thought to be in proximity to the CD3 signal-transduction complex.<ref name="pmid10318939">{{cite journal | vauthors = Kieke MC, Shusta EV, Boder ET, Teyton L, Wittrup KD, Kranz DM | title = Selection of functional T cell receptor mutants from a yeast surface-display library | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 10 | pages = 5651–6 | date = May 1999 | pmid = 10318939 | pmc = 21915 | doi = 10.1073/pnas.96.10.5651 }}</ref> CDR3 is the main CDR responsible for recognizing [[antigen processing|processed antigen]], although CDR1 of the alpha chain has also been shown to interact with the [[N-terminal]] part of the antigenic peptide, whereas CDR1 of the β-chain interacts with the [[C-terminal]] part of the peptide.

CDR2 is thought to recognize the MHC. CDR4 of the β-chain is not thought to participate in antigen recognition, but has been shown to interact with [[superantigen]]s.

The constant domain of the TCR consists of short connecting sequences in which a cysteine residue forms disulfide bonds, which form a link between the two chains.

The TCR is a member of the [[immunoglobulin superfamily]], a large group of proteins involved in binding, recognition, and adhesion; the family is named after [[antibodies]] (also called immunoglobulins). The TCR is similar to a half-antibody consisting of a single heavy and single light chain, except the heavy chain is without its crystallisable fraction (Fc). The two subunits of TCR are twisted together. Whereas the antibody uses its Fc region to bind to Fc Receptors on leukocytes, TCR is already docked onto the cell membrane. However, it is not able to mediate signal transduction itself due to its short cytoplasmic tail, so TCR still requires CD3 and zeta to carry out the signal transduction in its place, just as antibodies require binding to FcRs to initiate signal transduction. In this way the MHC-TCR-CD3 interaction for T cells is functionally similar to the antigen(Ag)-immunoglobulin(Ig)-FcR interaction for myeloid leukocytes, and Ag-Ig-CD79 interaction for B cells.

==Generation of the TCR diversity==
The generation of TCR diversity is similar to that for [[antibodies]] and [[B cell receptor|B cell antigen receptors]]. It arises mainly from [[genetic recombination]] of the DNA encoded segments in individual somatic T cells by [[V(D)J recombination|somatic V(D)J recombination]] using [[RAG1]] and [[RAG2]] recombinases. Unlike [[immunoglobulin]]s, however, TCR genes do not undergo somatic hypermutation, and T cells do not express [[activation-induced cytidine deaminase]](AID). The recombination process that creates diversity in [[B-cell receptor|BCR]] ([[Antibody|antibodies]]) and TCR is unique to [[lymphocyte]]s (T and B cells) during the early stages of their development in primary lymphoid organs ([[thymus]] for T cells, [[bone marrow]] for B cells).

Each recombined TCR possess unique [[antigen]] specificity, determined by the structure of the [[Complementarity determining region|antigen-binding site]] formed by the α and β chains in case of αβ T cells or γ and δ chains on case of γδ T cells.<ref name="Janeway Immunobiology - TCR Generation">{{cite book| vauthors = Janeway CA, Travers P, Walport M |title=Immunobiology: The Immune System in Health and Disease. | edition = 5th |year=2001|publisher=Garland Science|location=Chapter 4, The Generation of Lymphocyte Antigen Receptors|url=https://www.ncbi.nlm.nih.gov/books/NBK10774/|display-authors=etal}}</ref>

* The TCR ''alpha chain'' is generated by [[V(D)J recombination|VJ recombination]], whereas the ''beta chain'' is generated by VDJ recombination (both involving a somewhat random joining of gene segments to generate the complete TCR chain).
* Likewise, generation of the TCR ''gamma chain'' involves VJ recombination, whereas generation of the TCR ''delta chain'' occurs by VDJ recombination.

The intersection of these specific regions (V and J for the alpha or gamma chain; V, D, and J for the beta or delta chain) corresponds to the CDR3 region that is important for peptide/MHC recognition (see above).

It is the unique combination of the segments at this region, along with [[palindromic]] and random nucleotide additions (respectively termed  "P-" and "N-"), which accounts for the even greater diversity of T-cell receptor specificity for processed antigenic peptides.

Later during development, individual [[Complementarity determining region|CDR loops]] of TCR can be re-edited in the periphery outside thymus by reactivation of recombinases using a process termed [[T cell receptor revision|TCR revision]] (editing) and change its antigenic specificity.

==The TCR complex==
The TCR receptor complex is an octomeric complex of variable TCR receptor α and β chains with three dimeric signaling modules [[CD3 receptor|CD3]]δ/ε, CD3γ/ε and [[CD247]] ζ/ζ or ζ/η.  Ionizable residues in the transmembrane domain of each subunit form a polar network of interactions that hold the complex together.<ref name="pmid12507424">{{cite journal | vauthors = Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW | title = The organizing principle in the formation of the T cell receptor-CD3 complex | journal = Cell | volume = 111 | issue = 7 | pages = 967–79 | date = December 2002 | pmid = 12507424 | pmc = 3420808 | doi = 10.1016/s0092-8674(02)01194-7 }}</ref> Since the [[cytoplasmic]] tail of the TCR is extremely short, making it unlikely to participate in signaling, these signaling molecules are vital in propagating the signal from the triggered TCR into the cell.

Each T cell expresses clonal TCRs which recognize specific peptide/MHC complex during physical contact between T cell and [[antigen-presenting cell]]-APC ([[MHC class II]]) or any other cell type ([[MHC class I]]) <ref name="pmid19132916">{{cite journal | vauthors = Smith-Garvin JE, Koretzky GA, Jordan MS | title = T cell activation | journal = Annual Review of Immunology | volume = 27 | issue =  | pages = 591–619 | year = 2009 | pmid = 19132916 | pmc = 2740335 | doi = 10.1146/annurev.immunol.021908.132706 }}</ref> 
High on-rate and off-rate is characteristic for TCR and peptide/MHC interaction at physiological temperature. TCRs have very high degree of antigen specificity, despite of fact that the affinity to the  peptide/MHC ligand is in the micromolar range.<ref name="pmid17082606">{{cite journal | vauthors = Donermeyer DL, Weber KS, Kranz DM, Allen PM | title = The study of high-affinity TCRs reveals duality in T cell recognition of antigen: specificity and degeneracy | journal = Journal of Immunology | volume = 177 | issue = 10 | pages = 6911–9 | date = November 2006 | pmid = 17082606 | doi = 10.4049/jimmunol.177.10.6911 }}</ref> This weak binding (<math>K_D</math> dissociation constant values) between TCR and peptide/MHC was determined by the [[surface plasmon resonance]] (SPR) to be in the range 1-100 μM, the association constant in the range from 1000 to 10000 &nbsp;M<sup>−1</sup>×s<sup>−1</sup>,<ref name="pmid17442956">{{cite journal | vauthors = Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, Price DA, Gao GF, Sewell AK, Jakobsen BK | title = Human TCR-binding affinity is governed by MHC class restriction | journal = Journal of Immunology | volume = 178 | issue = 9 | pages = 5727–34 | date = May 2007 | pmid = 17442956 | doi = 10.4049/jimmunol.178.9.5727 }}</ref> The TCR affinity for peptided/MHC has a direct impact on modulation of T-cell function.
T cells are very sensitive to their antigens despite the low affinity of TCR for its peptide/MHC and low numbers of specific peptide/MHC on the surface of target cells.<ref name="pmid21365321">{{cite journal | vauthors = Edwards LJ, Evavold BD | title = T cell recognition of weak ligands: roles of signaling, receptor number, and affinity | journal = Immunologic Research | volume = 50 | issue = 1 | pages = 39–48 | date = May 2011 | pmid = 21365321 | pmc = 3107861 | doi = 10.1007/s12026-011-8204-3 }}</ref> 
The specific and efficient signaling via TCR might be regulated by dynamic oligomerization into TCR microclusters on the surface of T cells.<ref name="pmid23278737">{{cite journal | vauthors = Schamel WW, Alarcón B | title = Organization of the resting TCR in nanoscale oligomers | journal = Immunological Reviews | volume = 251 | issue = 1 | pages = 13–20 | date = January 2013 | pmid = 23278737 | doi = 10.1111/imr.12019 }}</ref> In this scenario, T-cell sensitivity to antigen could be increased via [[avidity]]-based mechanism. 
The antigen sensitivity is higher in antigen-experienced T cells than in naive T cells. Naive T cells pass through the process of functional avidity maturation with no change in affinity. It is based on the fact that effector and memory (antigen-experienced) T cell are less dependent on costimulatory signals and higher antigen concentration than naive T cell.<ref name="pmid22611418">{{cite journal | vauthors = von Essen MR, Kongsbak M, Geisler C | title = Mechanisms behind functional avidity maturation in T cells | journal = Clinical & Developmental Immunology | volume = 2012 | issue =  | pages = 163453 | year = 2012 | pmid = 22611418 | pmc = 3351025 | doi = 10.1155/2012/163453 }}</ref>

[[Image:63-T-CellReceptor-MHC.tif|thumb|T-Cell Receptor complexed with MHC I and II]]

==TCR co-receptors==
The signal from the T-cell complex is enhanced by simultaneous binding of the MHC molecules by a specific [[co-receptor]].

* On [[helper T cells]] and [[regulatory T cells]], this co-receptor is [[CD4]] that is specific for [[MHC class II]].
* On  [[cytotoxic T cells]], this co-receptor is [[CD8]] that is specific for [[MHC class I]].

Extracellularly, the TCR co-receptor defines the specificity of the TCR to MHC class I or II molecule, and increases binding affinity of TCR to MHC to prolong the cell-cell interaction between the [[antigen-presenting cell]] and the T cell.

Intracellularly, the TCR co-receptor recruits essential molecules (e.g., [[Lck|LCK]]) involved in the signaling of the activated T lymphocyte to facilitate the CD3 signal transduction mechanism.
[[File:Homo sapiens CD8 molecule.png|thumb|alt=alt text|'''Crystal structure of human CD8 molecule''' Only a fragment of extracellular portion of human CD8α is shown. Co-receptor CD8 bind class I MHC specifically]]

==Associated molecules of the TCR complex involved in T-cell activation==
The essential function of the TCR complex is to identify specific bound antigen and elicit a distinct and critical response. The signal transduction mechanism by which a T cell elicits this response upon contact with its unique antigen is termed T-cell activation (just as phototransduction is the term given to the signal transduction event by which photoreceptors elicits vision upon exposure to photons). There are myriad molecules involved in the complex biochemical process (called [[Signal transduction|trans-membrane signaling]]) by which T-cell activation occurs.

The most common mechanism for activation and regulation of molecules beneath the lipid bilayer is via reversible tyrosine phosphorylation by protein kinase/phosphatase. T cells utilise the [[Src family kinase]]s in transmembrane signalling largely to phosphorylate tyrosines that are part of [[immunoreceptor tyrosine-based activation motif]]s (ITAM) in intracellular parts of CD3 and ζ chains.<ref name="pmid17356173">{{cite journal | vauthors = Abram CL, Lowell CA | title = The expanding role for ITAM-based signaling pathways in immune cells | journal = Science's STKE | volume = 2007 | issue = 377 | pages = re2 | date = March 2007 | pmid = 17356173 | doi = 10.1126/stke.3772007re2 }}</ref>

Early signaling steps implicate the following kinases and phosphatases after TCR triggering:

* [[Lck]] – a Src family kinase associated with the intracellular tail of CD4 that phosphorylates CD3 and ζ ITAMs of the TCR complex
* [[FYN]] – a Src family kinase that phosphorylates CD3 and ζ ITAMs
* [[CD45]] – a transmembrane protein whose intracellular tail functions as a tyrosine phosphatase that activates Src family kinases
* [[Zap70]] – a Syk family kinase that binds to ITAM sequences upon tyrosine phosphorylation by Lck and Fyn, and phosphorylates LAT

When a T-cell receptor is activated by contact with a peptide:MHC complex, CD45 dephosphorylates inhibitory tyrosine of membrane-localized [[Src family kinase]]s Fyn and Lck, previously recruited and activated by CD4 or CD8 coreceptors. Activated Fyn and Lck phosphorylates ITAMs on the CD3 and ζ chains. This allows cytoplasmic kinases of the Syk family (ZAP-70) to bind to the ITAM and activated ZAP-70 phosphorylates tyrosines on the adaptor protein [[Linker of activated T cells|LAT]], which then attracts [[PLCG1|PLC-γ]]. Other downstream pathways are triggered as well ([[Mitogen-activated protein kinase|MAPK]], [[NF-κB]], [[NFAT]]) which results in gene transcription in the nucleus.<ref>{{cite book|last=Parham|first=Peter|title=The Immune System|year=2009|publisher=Garland Science|location=New York|isbn=978-0-8153-4146-8|pages=22–223}}</ref>

== See also ==
* [[ImmTAC]]
* [[Co-stimulation]]
* [[MHC multimer]]

== References ==
{{Reflist|32em}}

==External links==
{{Commonscat}}
*[http://www.tcells.org/scientific/abTCR/ T-cell Group – Cardiff University]
*{{UMichOPM|protein|pdbid|2hac}} – Zeta-zeta dimer of T cell receptor
*{{MeshName|T-Cell+Receptor}}

{{Immune receptors}}
{{Use dmy dates|date=February 2011}}

{{DEFAULTSORT:T Cell Receptor}}
[[Category:Cell signaling]]
[[Category:T cells|Receptor]]
[[Category:Single-pass transmembrane proteins]]