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| {{Infobox protein family
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| | Symbol =
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| | Name =
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| | image = TCRComplex.png
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| | width =
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| | caption = The '''T-cell receptor complex''' with TCR-α and TCR-β chains, [[CD3 receptor|CD3]] and ζ-chain accessory molecules.
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| | Pfam = PF11628
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| | Pfam_clan =
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| | InterPro = IPR021663
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| | SMART =
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| | PROSITE =
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| | MEROPS =
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| | SCOP =
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| | TCDB =
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| | OPM family = 261
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| | OPM protein = 2hac
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| | CAZy =
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| | CDD =
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| }}
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| [[File:Antigen presentation.svg|thumb|300px|Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.]] | |
| {{Infobox protein
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| | Name = T cell receptor alpha locus
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| | caption =
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| | image =
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| | width =
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| | HGNCid = 12027
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| | Symbol = TRA@
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| | AltSymbols = TCRA
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| | EntrezGene = 6955
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| | OMIM = 186880
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| | RefSeq =
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| | UniProt =
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| | PDB =
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| | ECnumber =
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| | Chromosome = 14
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| | Arm = q
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| | Band = 11.2
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| | LocusSupplementaryData =
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| }}
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| {{Infobox protein
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| | Name = T cell receptor beta locus
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| | caption =
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| | image =
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| | width =
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| | HGNCid = 12155
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| | Symbol = TRB@
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| | AltSymbols = TCRB
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| | EntrezGene = 6957
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| | OMIM = 186930
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| | RefSeq =
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| | UniProt =
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| | PDB =
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| | ECnumber =
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| | Chromosome = 7
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| | Arm = q
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| | Band = 34
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| | LocusSupplementaryData =
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| }}
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| The '''T cell receptor''' or '''TCR''' is a molecule found on the surface of [[T lymphocytes]] (or T cells)<ref name="KindtGoldsby2007">{{cite book|author1=Thomas J. Kindt|author2=Richard A. Goldsby|author3=Barbara Anne Osborne|coauthors=Janis Kuby|title=Kuby immunology|url=http://books.google.com/books?id=oOsFf2WfE5wC&pg=PA223|accessdate=28 November 2010|year=2007|publisher=Macmillan|isbn=978-1-4292-0211-4|pages=223–}}</ref> that is responsible for recognizing [[antigen]]s bound to [[major histocompatibility complex]] (MHC) molecules. The binding between TCR and antigen is of relatively low [[Affinity (pharmacology)#Protein-ligand binding|affinity]] and is [[degeneracy (biology)|degenerate]]: that is, many TCR recognize the same antigen and many antigens are recognized by the same TCR.
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| The TCR is composed of two different protein chains (that is, it is a [[heteromer|hetero]][[protein dimer|dimer]]). In 95% of T cells, this consists of an alpha (α) and beta (β) chain, whereas in 5% of T cells this consists of [[gamma/delta T cells|gamma and delta]] (γ/δ) chains. This ratio changes during ontogeny and in diseased states.
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| When the TCR engages with antigenic peptide and MHC (peptide/MHC), the T lymphocyte is activated through a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors.
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| ==Structural characteristics of the TCR==
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| The TCR is a disulfide-linked membrane-anchored heterodimer 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|last=Janeway CA Jr, Travers P, Walport M, et al.|title=Immunobiology: The Immune System in Health and Disease. 5th edition|year=2001|publisher=Garland Science|location=Glossary|url=http://www.ncbi.nlm.nih.gov/books/NBK10759/def-item/A3289/?report=objectonly}}</ref>
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| 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.
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| The variable domain of both the TCR α-chain and β-chain have three hypervariable or [[complementarity determining region]]s (CDRs), whereas the variable region of the β-chain has an additional area of hypervariability (HV4) that does not normally contact antigen and, therefore, is not considered a CDR.
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| The residues 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 | author = 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 = Proc. Natl. Acad. Sci. U.S.A. | 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.
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| 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.
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| The constant domain of the TCR domain consists of short connecting sequences in which a cysteine residue forms disulfide bonds, which forms a link between the two chains.
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| ==Generation of the TCR diversity==
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| Processes for the generation of TCR diversity are similar to those described for [[B cell receptor|B cell antigen receptors]], otherwise known as [[immunoglobulin]]s. It is based mainly on somatic recombination of the DNA encoded segments in individual T cells.
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| TCRs possess unique antigen specificity, determined by the structure of the antigen-binding site formed by the α and β chains.<ref name="Janeway Immunobiology - TCR Generation">{{cite book|last=Janeway CA Jr, Travers P, Walport M, et al.|title=Immunobiology: The Immune System in Health and Disease. 5th edition|year=2001|publisher=Garland Science|location=Chapter 4, The Generation of Lymphocyte Antigen Receptors|url=http://www.ncbi.nlm.nih.gov/books/NBK10774/}}</ref>
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| * 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).
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| * Likewise, generation of the TCR ''gamma chain'' involves VJ recombination, whereas generation of the TCR ''delta chain'' occurs by VDJ recombination.
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| 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).
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| 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 great diversity in specificity of the T cell receptor for processed antigen.
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| ==The TCR complex==
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| 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 | author = 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 | doi = }}</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.
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| Each T cell express clonal TCR 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 | author = Smith-Garvin JE, Koretzky GA, Jordan MS | title = T cell activation | journal = Annu. Rev. Immunol. | volume = 27 | issue = | pages = 591–619 | year = 2009 | pmid = 19132916 | pmc = 2740335 | doi = 10.1146/annurev.immunol.021908.132706 }}</ref>
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| High on-rate and off-rate is characteristic for TCR and peptide/MHC interaction at physiological temperature. TCRs have very high degree of antigen specifity, despite of fact that the affinity to the peptide/MHC ligand is in the micromolar range.<ref name="pmid17082606">{{cite journal | author = 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 = J. Immunol. | volume = 177 | issue = 10 | pages = 6911–9 |date=November 2006 | pmid = 17082606 | doi = }}</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 M<sup>−1</sup>×s<sup>−1</sup>,<ref name="pmid17442956">{{cite journal | author = 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 = J. Immunol. | volume = 178 | issue = 9 | pages = 5727–34 |date=May 2007 | pmid = 17442956 | doi = }}</ref> The TCR affinity for peptided/MHC has a direct impact on modulation of T cell function.
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| T cell are very sensitive to their antigens despite the low affinity of TCR for its peptide/MHC and low numbers of specific peptide/MHC an the surface of target cells.<ref name="pmid21365321">{{cite journal| author=Edwards LJ, Evavold BD| title=T cell recognition of weak ligands: roles of signaling, receptor number, and affinity. | journal=Immunol Res | year= 2011 | volume= 50 | issue= 1 | pages= 39–48 | pmid=21365321 | doi=10.1007/s12026-011-8204-3 | pmc=3107861 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21365321 }}</ref>
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| The specific and efficient signaling via TCR might be regulated by dynamic oligomerization into TCR microclusters on the surface of T cell.<ref name="pmid23278737">{{cite journal | author = Schamel WW, Alarcón B | title = Organization of the resting TCR in nanoscale oligomers | journal = Immunol. Rev. | 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.
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| 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 fact that effector amd memory (antigen-experienced) T cell are less dependent on costimulatory signals and higher antigen concentration than naive T cell.<ref name="pmid22611418">{{cite journal | author = von Essen MR, Kongsbak M, Geisler C | title = Mechanisms behind functional avidity maturation in T cells | journal = Clin. Dev. Immunol. | volume = 2012 | issue = | pages = 163453 | year = 2012 | pmid = 22611418 | pmc = 3351025 | doi = 10.1155/2012/163453 }}</ref>
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| ==TCR co-receptors==
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| The signal from the T cell complex is enhanced by simultaneous binding of the MHC molecules by a specific [[co-receptor]].
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| * On [[helper T cells]], this co-receptor is [[CD4]] that is specific for [[MHC class II]].
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| * On [[cytotoxic T cells]], this co-receptor is [[CD8]] that is specific for [[MHC class I]].
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| The co-receptor not only ensures the specificity of the TCR for an antigen but also allows prolonged engagement between the [[antigen-presenting cell]] and the T cell and recruits essential molecules (e.g., [[Lck|LCK]]) inside the cell involved in the signaling of the activated T lymphocyte.
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| [[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]]
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| ==Associated molecules of the TCR complex involved in T-cell activation==
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| The essential function of the TCR complex is to identify specific bound antigen and elicit a distinct and critical response. The mechanism by which a T-cell elicits this response upon contact with its unique antigen is termed T-cell activation. There are myriad molecules involved in the complex biochemical process by which this occurs, which, in a wider context, is, in general, termed trans-membrane signalling.
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| The most common mechanism for activation and regulation of molecules beneath the lipid bilayer is via phosphorylation/dephosphorylation by protein kinases. 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 | author = Abram CL, Lowell CA | title = The expanding role for ITAM-based signaling pathways in immune cells | journal = Sci. STKE | volume = 2007 | issue = 377 | pages = re2 |date=March 2007 | pmid = 17356173 | doi = 10.1126/stke.3772007re2 }}</ref>
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| Early signaling steps implicate the following kinases and phosphatases after TCR triggering:
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| * [[Lck]] – [[Src family kinase]] associated with the intracellular tail of CD4 and phosphorylate ITAMs
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| * [[Fyn]] – [[Src family kinase]] phosphoorylate ITAMs of the CD3 and ζ ITAMs of the TCR complex
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| * [[CD45]] – The intracellular tail function as a tyrosine phosphatase activating Src family kinases
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| * [[Zap70]] – Syk family kinase bind to ITAM sequences upon tyrosine phosphorylation by Lck and Fyn and phosphorylate LAT
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| 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 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>
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| ==References==
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| {{Reflist|35em}}
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| ==External links==
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| * [http://www.tcells.org/scientific/abTCR/ T-cell Group – Cardiff University]
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| * {{UMichOPM|protein|pdbid|2hac}} – Zeta-zeta dimer of T cell receptor
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| * {{MeshName|T-Cell+Receptor}}
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| ==See also==
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| * [[T cell]]
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| * [[ImmTAC]]
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| * [[Co-stimulation]]
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| * [[MHC multimer]]
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| {{Immune receptors}}
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| {{Use dmy dates|date=February 2011}}
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| {{DEFAULTSORT:T Cell Receptor}}
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| [[Category:Cell signaling]]
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| [[Category:T cells]]
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| [[Category:Integral membrane proteins]]
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