The T-cell receptor complex with TCR-α and TCR-β chains, CD3 and ζ-chain accessory molecules. |
| Identifiers |
| Pfam |
PF11628 |
| InterPro |
IPR021663 |
| OPM superfamily |
261 |
| OPM protein |
2hac |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe |
| PDBsum |
structure summary |
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Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.
| T cell receptor alpha locus |
| Identifiers |
| Symbol |
TRA@ |
| Alt. symbols |
TCRA |
| Entrez |
6955 |
| HUGO |
12027 |
| OMIM |
186880 |
| Other data |
| Locus |
Chr. 14 q11.2 |
| T cell receptor beta locus |
| Identifiers |
| Symbol |
TRB@ |
| Alt. symbols |
TCRB |
| Entrez |
6957 |
| HUGO |
12155 |
| OMIM |
186930 |
| Other data |
| Locus |
Chr. 7 q34 |
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells)[1] that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen is of relatively low affinity and is degenerate: that is, many TCR recognize the same antigen and many antigens are recognized by the same TCR.
The TCR is composed of two different protein chains (that is, it is a heterodimer). 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 and delta (γ/δ) chains.
When the TCR engages with antigen and MHC, the T lymphocyte is activated through a series of biochemical events mediated by associated enzymes, co-receptors, specialized accessory molecules, and activated or released transcription factors.
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Contents
- 1 Structural characteristics of the TCR
- 2 Generation of the TCR
- 3 The TCR complex
- 4 TCR co-receptors
- 5 Associated molecules of the TCR complex involved in T-cell activation
- 6 References
- 7 External links
- 8 See also
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Structural characteristics of the TCR[edit]
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 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.[2]
Each chain is composed of a Variable (V) region and a Constant (C) region. The Constant region anchors the TCR to the cell membrane, including a short cytoplasmic tail, while the extracellular Variable region binds to the antigen:MHC complex. MHC is also referred to in humans as the Human leukocyte antigen.
The variable domain of both the TCR α-chain and β-chain have three hypervariable or complementarity determining regions (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.
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.[3] CDR3 is the main CDR responsible for recognizing 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 superantigens.
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.
Generation of the TCR[edit]
Processes for TCR formation are similar to those described for B cell antigen receptors, otherwise known as immunoglobulins.
TCRs possess unique antigen specificity, determined by the structure of the antigen-binding site formed by the alpha and beta chains.[4]
- The TCR alpha chain is generated by 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 antigen-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 great diversity in specificity of the T cell receptor for processed antigen.
The TCR complex[edit]
It is thought that such structure allows the TCR to associate with other molecules like CD3, which possess three distinct chains (γ, δ, and ε) in mammals, and either a ζ2 (CD247) complex or a ζ/η complex.
These accessory molecules have transmembrane regions and are vital to propagating the signal from the TCR into the cell; the cytoplasmic tail of the TCR is extremely short, making it unlikely to participate in signaling.
The CD3- and ζ-chains, together with the TCR, form what is known as the T cell receptor complex.
TCR co-receptors[edit]
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, this co-receptor is CD4 that is specific for class II MHC.
- On cytotoxic T cells, this co-receptor is CD8 that is specific for class I MHC.
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) inside the cell involved in the signaling of the activated T lymphocyte.
Crystal structure of human CD8 molecule Only a fragment of extracellular portion of human CD8a is shown. Co-receptor CD 8 could bind class I MHC specifically
Associated molecules of the TCR complex involved in T-cell activation[edit]
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.
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 of kinases in transmembrane signalling largely to phosphorylate tyrosines that are part of immunoreceptor tyrosine-based activation motifs (ITAM).[5]
Early signaling steps implicate the following kinases in TCR associated reactions.
- Lck – Associated with the transmembrane tail of CD4
- Fyn – Associated with ITAMs of the IgAlpha and Igbeta regions of the TCR complex
- CD45 – The transmembrane tail of which functions as a Tyrosine phosphatase)
- Zap70 – Binds to ITAM sequences upon phosphorylation by Lck and Fyn
When a T cell receptor is activated by contact with a peptide:MHC complex, CD45 dephosphorylates Fyn, activating it. Fyn phosphorylates the ITAMs on the CD3 and ζ chains. This allows other kinases like ZAP-70 to bind on the ITAM, localizing it near Lck, previously recruited and activated by CD4 or 8. Lck phosphorylates ZAP-70, and activated ZAP-70 will go on to indirectly activate PLC-γ and result in gene transcription in the nucleus.[6] This is accomplished through an adaptor protein like LAT, which brings together the activate ZAP-70 and PLC-γ.
References[edit]
- ^ Thomas J. Kindt; Richard A. Goldsby; Barbara Anne Osborne; Janis Kuby (2007). Kuby immunology. Macmillan. pp. 223–. ISBN 978-1-4292-0211-4. Retrieved 28 November 2010.
- ^ Janeway CA Jr, Travers P, Walport M, et al. (2001). Immunobiology: The Immune System in Health and Disease. 5th edition. Glossary: Garland Science.
- ^ Kieke, Michele C.; Shusta, Eric V.; Teyton, Luc; Wittrup, K. Dane; Kranz, David M. (1999). "Selection of functional T cell receptor mutants from a yeast surface-display library". Proceedings of the National Academy of Science of the United States of America 96 (10): 5651–5656. doi:10.1073/pnas.96.10.5651
- ^ Janeway CA Jr, Travers P, Walport M, et al. (2001). Immunobiology: The Immune System in Health and Disease. 5th edition. Chapter 4, The Generation of Lymphocyte Antigen Receptors: Garland Science.
- ^ Abram, Clare L.; Lowell, Clifford A. (2007-03-13). "The Expanding Role for ITAM-Based Signaling Pathways in Immune Cells". Science Signalling 2007 (377): re2.
- ^ Parham, Peter (2009). The Immune System. New York: Garland Science. pp. 22–223. ISBN 978-0-8153-4146-8.
External links[edit]
- T-cell Group – Cardiff University
- UMich Orientation of Proteins in Membranes protein/pdbid-2hac – Zeta-zeta dimer of T cell receptor
- T-Cell Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
See also[edit]
- T cell
- Co-stimulation
- MHC multimer
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Transmembrane receptors: Immunoglobulin superfamily immune receptors
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Antibody receptor:
Fc receptor |
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Epsilon (ε)
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FcεRI · (FcεRII is C-type lectin)
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Gamma (γ)
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FcγRI · FcγRII · FcγRIII · Neonatal
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Alpha (α)/mu (μ)
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FcαRI · Fcα/μR
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Secretory
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Polymeric immunoglobulin receptor
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| Antigen receptor |
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B cells
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Antigen receptor
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BCR
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Co-receptor
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stimulate: CD21/CD19/CD81
inhibit: CD22
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Accessory molecules
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Ig-α/Ig-β (CD79)
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T cells
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Ligands
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MHC (MHC class I and MHC class II)
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Antigen receptor
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TCR: TRA@ · TRB@ · TRD@ · TRG@
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Co-receptors
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CD8 (with two glycoprotein chains CD8α and CD8β) · CD4
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Accessory molecules
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CD3 · CD3γ · CD3δ · CD3ε · ζ-chain (also called CD3ζ and TCRζ)
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| Cytokine receptor |
see cytokine receptors
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| Killer-cell IG-like receptors |
KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL2, KIR3DL3, KIR3DS1
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| Leukocyte IG-like receptors |
LILRA1 · LILRA2 · LILRA3 · LILRA4 · LILRA5 · LILRA6 · LILRB1 · LILRB2 · LILRB3 · LILRB4 · LILRB5 · LILRA6 · LILRA5
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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cell/phys/auag/auab/comp, igrc
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