Tcellreceptor

The Tcellreceptor, or TCR, is a molecule found on the surface of T cells,

or T lymphocytes,[1] 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
and is degenerate: that is, many TCRs recognize the same antigen peptide
and many antigen peptides are recognized by the same TCR.[2]

The TCR is composed of two different protein chains (that is, it is a

heterodimer). In humans, in 95% of T cells the TCR consists of an alpha () The T-cell receptor complex with
chain and a beta () chain (encoded by TRA and TRB, respectively), whereas TCR- and TCR- chains, CD3 and -
in 5% of T cells the TCR consists of gamma and delta (/) chains (encoded chain accessory molecules.
by TRG and TRD, respectively). This ratio changes during ontogeny and in
Identiers
diseased states (such as leukemia). It also differs between species.
Orthologues of the 4 loci have been mapped in various species.[3][4] Each
Symbol TCR_zetazeta
locus can produce a variety of polypeptides with constant and variable Pfam PF11628 (http://pfam.xf
regions.[3] am.org/family?acc=PF1
1628)
When the TCR engages with antigenic peptide and MHC (peptide/MHC), the
InterPro IPR021663 (https://ww
T lymphocyte is activated through signal transduction, that is, a series of
w.ebi.ac.uk/interpro/entr
biochemical events mediated by associated enzymes, co-receptors,
y/IPR021663)
specialized adaptor molecules, and activated or released transcription
factors. OPM 261 (http://opm.phar.um
superfamily ich.edu/families.php?su
perfamily=261)
OPM 2hac (http://opm.phar.u
Contents protein mich.edu/protein.php?s
earch=2hac)
1 History of the TCR
Available protein structures:
2 Structural characteristics of the TCR
Pfam structures (http://pfam.xfam.or
3 Generation of the TCR diversity
g/family/PF11628?tab=pdbBlo
4 The TCR complex ck)
5 TCR co-receptors
PDB RCSB PDB (http://www.rcsb.o
6 rg/pdb/search/smartSubquery.
Associated molecules of the TCR complex involved in T-cell do?smartSearchSubtype=Pfa
activation
mIdQuery&pfamID=PF11628);
7 See also PDBe (https://www.ebi.ac.uk/
8 References pdbe/entry/search/index?pfa
9 External links m_accession:PF11628); PDBj
(https://pdbj.org/searchFor?qu
ery=PF11628)

PDBsum structure summary (https://ww

HistoryoftheTCR w.ebi.ac.uk/thornton-srv/datab
ases/cgi-bin/pdbsum/GetPfam
In 1984, Tak Wah Mak[5] and Mark M. Davis[6] discovered the human and
Str.pl?pfam_id=PF11628)
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.
Structuralcharacteristicsof
theTCR
The TCR is a disulfide-linked membrane-anchored heterodimeric
protein normally consisting of the highly variable alpha () and
beta () chains expressed as part of a complex with the invariant
CD3 chain molecules. T cells expressing this receptor are referred
to as : (or ) T cells, though a minority of T cells express an
alternate receptor, formed by variable gamma () and delta ()
chains, referred as T cells.[7]

Each chain is composed of two extracellular domains: Variable Antigen presentation stimulates T cells to become
either "cytotoxic" CD8+ cells or "helper" CD4+
(V) region and a Constant (C) region, both of Immunoglobulin
cells.
superfamily (IgSF) domain forming antiparallel -sheets. The
Constant region is proximal to the cell membrane, followed by a
transmembrane region and a short cytoplasmic tail, while the Variable region
T-cell receptor alpha locus
binds to the peptide/MHC complex.
Identiers
The variable domain of both the TCR -chain and -chain each have three Symbol TRA
hypervariable or complementarity determining regions (CDRs). There is also Alt. TCRA, TRA@
an additional area of hypervariability on the -chain (HV4) that does not symbols
normally contact antigen and, therefore, is not considered a CDR.
Entrez 6955 (https://www.ncbi.nl
The residues in these variable domains are located in two regions of the TCR, m.nih.gov/gene?cmd=ret
at the interface of the - and -chains and in the -chain framework region rieve&dopt=default&list_
that is thought to be in proximity to the CD3 signal-transduction complex.[8] uids=6955&rn=1)
CDR3 is the main CDR responsible for recognizing processed antigen, HUGO 12027 (http://www.genen
although CDR1 of the alpha chain has also been shown to interact with the N- ames.org/data/hgnc_dat
terminal part of the antigenic peptide, whereas CDR1 of the -chain interacts a.php?hgnc_id=12027)
with the C-terminal part of the peptide.
OMIM 186880 (https://www.omi
CDR2 is thought to recognize the MHC. CDR4 of the -chain is not thought to m.org/186880)
participate in antigen recognition, but has been shown to interact with Other data
superantigens. Locus Chr. 14 q11.2 (https://omi
m.org/search?index=gen
The constant domain of the TCR consists of short connecting sequences in
eMap&search=14q11.2)
which a cysteine residue forms disulfide bonds, which form a link between the
two chains.
T-cell receptor beta locus
The TCR is a member of the immunoglobulin superfamily, a large group of Identiers
proteins involved in binding, recognition, and adhesion; the family is named
Symbol TRB
after antibodies (also called immunoglobulins). The TCR is similar to a half-
Alt. TCRB, TRB@
antibody consisting of a single heavy and single light chain, except the heavy
symbols
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 Entrez 6957 (https://www.ncbi.nl
Receptors on leukocytes, TCR is already docked onto the cell membrane. m.nih.gov/gene?cmd=ret
However, it is not able to mediate signal transduction itself due to its short rieve&dopt=default&list_
cytoplasmic tail, so TCR still requires CD3 and zeta to carry out the signal uids=6957&rn=1)
transduction in its place, just as antibodies require binding to FcRs to initiate HUGO 12155 (http://www.genen
signal transduction. In this way the MHC-TCR-CD3 interaction for T cells is ames.org/data/hgnc_dat
functionally similar to the antigen(Ag)-immunoglobulin(Ig)-FcR interaction a.php?hgnc_id=12155)
for myeloid leukocytes, and Ag-Ig-CD79 interaction for B cells.
OMIM 186930 (https://www.omi
GenerationoftheTCRdiversity m.org/186930)
Other data
The generation of TCR diversity is similar to that for antibodies and B cell
Locus Chr. 7 q34 (https://omim.
antigen receptors. It arises mainly from genetic recombination of the DNA
org/search?index=geneM
encoded segments in individual somatic T cells by somatic V(D)J
ap&search=7q34)
recombination using RAG1 and RAG2 recombinases. Unlike immunoglobulins,
however, TCR genes do not undergo somatic hypermutation, and T cells do not
express Activation-Induced (Cytidine) Deaminase (AID). The recombination
T-cell receptor delta locus
process that creates diversity in BCR (antibodies) and TCR is unique to Identiers
lymphocytes (T and B cells) during the early stages of their development in Symbol TRD
primary lymphoid organs (thymus for T cells, bone marrow for B cells). Alt. TCRD, TRD@, TCRDV1
symbols
Each recombined TCR possess unique antigen specificity, determined by the
structure of the antigen-binding site formed by the and chains in case of Entrez 6964 (https://www.ncbi.nl
T cells or and chains on case of T cells.[9] m.nih.gov/gene?cmd=ret
rieve&dopt=default&list_
The TCR alpha chain is generated by VJ recombination, whereas the beta uids=6964&rn=1)
chain is generated by VDJ recombination (both involving a somewhat
random joining of gene segments to generate the complete TCR chain). HUGO 12252 (http://www.genen
Likewise, generation of the TCR gamma chain involves VJ recombination, ames.org/data/hgnc_dat
whereas generation of the TCR delta chain occurs by VDJ recombination.
a.php?hgnc_id=12252)
The intersection of these specific regions (V and J for the alpha or gamma
Other data
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). Locus Chr. 14 q11.2 (https://omi
m.org/search?index=gen
It is the unique combination of the segments at this region, along with eMap&search=14q11.2)
palindromic and random nucleotide additions (respectively termed "P-" and
"N-"), which accounts for the even greater diversity of T-cell receptor T-cell receptor gamma
specificity for processed antigenic peptides. locus
Later during development, individual CDR loops of TCR can be re-edited in the
Identiers
periphery outside thymus by reactivation of recombinases using a process Symbol TRG
termed TCR revision (editing) and change its antigenic specificity. Alt. TCRG, TRG@
symbols
TheTCRcomplex Entrez 6965 (https://www.ncbi.nl
m.nih.gov/gene?cmd=ret
The TCR receptor complex is an octomeric complex of variable TCR receptor
rieve&dopt=default&list_
and chains with three dimeric signaling modules CD3/, CD3/ and
uids=6965&rn=1)
CD247 / or /. Ionizable residues in the transmembrane domain of each
subunit form a polar network of interactions that hold the complex HUGO 12271 (http://www.genen
together.[10] Since the cytoplasmic tail of the TCR is extremely short, making it ames.org/data/hgnc_dat
unlikely to participate in signaling, these signaling molecules are vital in a.php?hgnc_id=12271)
propagating the signal from the triggered TCR into the cell. Other data
Locus Chr. 7 p14 (https://omim.
Each T cell expresses clonal TCRs which recognize specific peptide/MHC
org/search?index=geneM
complex during physical contact between T cell and antigen-presenting cell-
[11] ap&search=7p14)
APC (MHC class II) or any other cell type (MHC class I) 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.[12] This weak binding ( dissociation constant values) between TCR and peptide/MHC was
determined by the surface plasmon resonance (SPR) to be in the range 1-100 M, the association constant in the range
from 1000 to 10000 M1s1,[13] 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.[14] The specific and efficient signaling via TCR might be regulated
by dynamic oligomerization into TCR microclusters on the surface of T cells.[15] 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.[16]

TCRcoreceptors
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

specic for MHC class II.
On cytotoxic T cells, this co-receptor is CD8 that is specic for MHC class
I.
Extracellularly, the TCR co-receptor defines the specificity of the TCR to MHC
T-Cell Receptor complexed with
class I or II molecule, and increases binding affinity of TCR to MHC to prolong
MHC I and II
the cell-cell interaction between the antigen-presenting cell and the T cell.

Intracellularly, the TCR co-receptor recruits essential molecules (e.g., LCK)

involved in the signaling of the activated T lymphocyte to facilitate the CD3 signal transduction mechanism.

AssociatedmoleculesoftheTCR
complexinvolvedinTcellactivation
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 Crystal structure of human CD8
molecule Only a fragment of
process (called trans-membrane signaling) by which T-cell activation occurs.
extracellular portion of human CD8
The most common mechanism for activation and regulation of molecules is shown. Co-receptor CD8 bind
class I MHC specically
beneath the lipid bilayer is via reversible tyrosine phosphorylation by protein
kinase/phosphatase. T cells utilise the Src family kinases in transmembrane
signalling largely to phosphorylate tyrosines that are part of immunoreceptor tyrosine-based activation motifs (ITAM) in
intracellular parts of CD3 and chains.[17]

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 ITAMs of the
TCR complex
FYN a Src family kinase that phosphorylates CD3 and 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 kinases Fyn and Lck, previously recruited and activated by CD4 or CD8 coreceptors.
Activated Fyn and Lck phosphorylates ITAMs on the CD3 and 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 LAT, which then
attracts PLC-. Other downstream pathways are triggered as well (MAPK, NF-B, NFAT) which results in gene
transcription in the nucleus.[18]
Seealso
ImmTAC
Co-stimulation
MHC multimer

References
1. Thomas J. Kindt; Richard A. Goldsby; Barbara Anne Osborne; Janis Kuby (2007). Kuby immunology (https://books.g
oogle.com/books?id=oOsFf2WfE5wC&pg=PA223). Macmillan. pp.223. ISBN978-1-4292-0211-4. Retrieved
28 November 2010.
2. Sewell, AK (2012), "Why must T cells be cross-reactive", Nat Rev Imm, 12 (9): 669677, PMID22918468 (https://ww
w.ncbi.nlm.nih.gov/pubmed/22918468)
3. Glusman, G; et al. (2001), "Comparative genomics of the human and mouse T cell receptor loci", Immunity, 15 (3):
337349, PMID11567625 (https://www.ncbi.nlm.nih.gov/pubmed/11567625), doi:10.1016/s1074-7613(01)00200-x (ht
tps://doi.org/10.1016%2Fs1074-7613%2801%2900200-x).
4. Deakin, JE; et al. (2006), "Physical mapping of T cell receptor loci (TRA@, TRB@, TRD@ and TRG@) in the
opossum (Monodelphis domestica)", Cytogenet Genome Res, 112 (34): 342K, PMID16484802 (https://www.ncbi.nl
m.nih.gov/pubmed/16484802), doi:10.1159/000089901 (https://doi.org/10.1159%2F000089901).
5. Yanagi, Yusuke; Yoshikai, Yasunobu; Leggett, Kathleen; Clark, Stephen P.; Aleksander, Ingrid; Mak, Tak W. (1984-03-
08). "A human T cell-specic cDNA clone encodes a protein having extensive homology to immunoglobulin chains" (h
ttp://www.nature.com/nature/journal/v308/n5955/abs/308145a0.html?foxtrotcallback=true). Nature. 308 (5955): 145
149. doi:10.1038/308145a0 (https://doi.org/10.1038%2F308145a0).
6. Hedrick, Stephen M.; Cohen, David I.; Nielsen, Ellen A.; Davis, Mark M. (1984-03-08). "Isolation of cDNA clones
encoding T cell-specic membrane-associated proteins" (http://www.nature.com/nature/journal/v308/n5955/abs/3081
49a0.html?foxtrotcallback=true). Nature. 308 (5955): 149153. doi:10.1038/308149a0 (https://doi.org/10.1038%2F30
8149a0).
7. Janeway CA Jr; Travers P; Walport M; et al. (2001). Immunobiology: The Immune System in Health and Disease. 5th
edition (https://www.ncbi.nlm.nih.gov/books/NBK10759/def-item/A3289/?report=objectonly). Glossary: Garland
Science.
8. Kieke MC, Shusta EV, Boder ET, Teyton L, Wittrup KD, Kranz DM (May 1999). "Selection of functional T cell receptor
mutants from a yeast surface-display library" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21915). Proc. Natl.
Acad. Sci. U.S.A. 96 (10): 56516. PMC21915 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21915) .
PMID10318939 (https://www.ncbi.nlm.nih.gov/pubmed/10318939). doi:10.1073/pnas.96.10.5651 (https://doi.org/10.1
073%2Fpnas.96.10.5651).
9. Janeway CA Jr; Travers P; Walport M; et al. (2001). Immunobiology: The Immune System in Health and Disease. 5th
edition (https://www.ncbi.nlm.nih.gov/books/NBK10774/). Chapter 4, The Generation of Lymphocyte Antigen
Receptors: Garland Science.
10. Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW (December 2002). "The organizing principle in the formation of
the T cell receptor-CD3 complex." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420808). Cell. 111 (7): 96779.
PMC3420808 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420808) . PMID12507424 (https://www.ncbi.nlm.ni
h.gov/pubmed/12507424). doi:10.1016/s0092-8674(02)01194-7 (https://doi.org/10.1016%2Fs0092-8674%2802%290
1194-7).
11. Smith-Garvin JE, Koretzky GA, Jordan MS (2009). "T cell activation" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC
2740335). Annu. Rev. Immunol. 27: 591619. PMC2740335 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC274033
5) . PMID19132916 (https://www.ncbi.nlm.nih.gov/pubmed/19132916).
doi:10.1146/annurev.immunol.021908.132706 (https://doi.org/10.1146%2Fannurev.immunol.021908.132706).
12. Donermeyer DL, Weber KS, Kranz DM, Allen PM (November 2006). "The study of high-afnity TCRs reveals duality
in T cell recognition of antigen: specicity and degeneracy". J. Immunol. 177 (10): 69119. PMID17082606 (https://w
ww.ncbi.nlm.nih.gov/pubmed/17082606). doi:10.4049/jimmunol.177.10.6911 (https://doi.org/10.4049%2Fjimmunol.17
7.10.6911).
13. Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, Price DA, Gao GF, Sewell AK, Jakobsen BK (May
2007). "Human TCR-binding afnity is governed by MHC class restriction". J. Immunol. 178 (9): 572734.
PMID17442956 (https://www.ncbi.nlm.nih.gov/pubmed/17442956). doi:10.4049/jimmunol.178.9.5727 (https://doi.org/
10.4049%2Fjimmunol.178.9.5727).
14. Edwards LJ, Evavold BD (2011). "T cell recognition of weak ligands: roles of signaling, receptor number, and afnity."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107861). Immunol Res. 50 (1): 3948. PMC3107861 (https://www.n
cbi.nlm.nih.gov/pmc/articles/PMC3107861) . PMID21365321 (https://www.ncbi.nlm.nih.gov/pubmed/21365321).
doi:10.1007/s12026-011-8204-3 (https://doi.org/10.1007%2Fs12026-011-8204-3).
15. Schamel WW, Alarcn B (January 2013). "Organization of the resting TCR in nanoscale oligomers". Immunol. Rev.
251 (1): 1320. PMID23278737 (https://www.ncbi.nlm.nih.gov/pubmed/23278737). doi:10.1111/imr.12019 (https://doi.
org/10.1111%2Fimr.12019).
16. von Essen MR, Kongsbak M, Geisler C (2012). "Mechanisms behind functional avidity maturation in T cells" (https://w
ww.ncbi.nlm.nih.gov/pmc/articles/PMC3351025). Clin. Dev. Immunol. 2012: 163453. PMC3351025 (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC3351025) . PMID22611418 (https://www.ncbi.nlm.nih.gov/pubmed/22611418).
doi:10.1155/2012/163453 (https://doi.org/10.1155%2F2012%2F163453).
17. Abram CL, Lowell CA (March 2007). "The expanding role for ITAM-based signaling pathways in immune cells". Sci.
STKE. 2007 (377): re2. PMID17356173 (https://www.ncbi.nlm.nih.gov/pubmed/17356173).
doi:10.1126/stke.3772007re2 (https://doi.org/10.1126%2Fstke.3772007re2).
18. Parham, Peter (2009). The Immune System. New York: Garland Science. pp.22223. ISBN978-0-8153-4146-8.

Externallinks
T-cell Group Cardiff University (http://www.tcells.org/scientic/abTCR/)
UMich Orientation of Proteins in Membranes protein/pdbid-2hac (http://opm.phar.umich.edu/protein.php?pdbid=2hac)
Zeta-zeta dimer of T cell receptor
T-Cell Receptor (https://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=T-Cell+Receptor) at the US National
Library of Medicine Medical Subject Headings (MeSH)

Retrieved from "https://en.wikipedia.org/w/index.php?title=T-cell_receptor&oldid=801881421"

This page was last edited on 22 September 2017, at 14:21.

Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this
site, you agree to the Terms of Use and Privacy Policy. Wikipedia is a registered trademark of the Wikimedia
Foundation, Inc., a non-prot organization.