T cell receptor

Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.

The two chains of the T cell receptor

The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is, in general, responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules.

It is a heterodimer consisting of an alpha and beta chain in 95% of T cells, whereas 5% of T cells have TCRs consisting of gamma and delta chains.

Engagement of the TCR with antigen and MHC results in activation of its T lymphocyte through a series of biochemical events mediated by associated enzymes, co-receptors, specialized accessory molecules and activated or released transcription factors.

Structural characteristics of the TCR

The structure of TCR is very similar to immunoglobulin Fab fragments, which are regions defined as the combined light and heavy chain of an antibody arm. Each chain of the TCR is a member of the immunoglobulin superfamily and possesses one N-terminal immunoglobulin (Ig)-variable (V) domain, one Ig-constant (C) domain, a transmembrane/cell membrane-spanning region, and a short cytoplasmic tail at the C-terminal end.

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 alpha - and Beta-chains and in the beta-chain framework region that is thought to be in proximity to the CD3 signal-transduction complex ^[1]. 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 beta 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

Processes for TCR formation are similar to those described for B cell antigen receptors, otherwise known as immunoglobulins.

• The TCR alpha chain is generated by VJ recombination, whereas the beta chain is generated by V(D)J recombination (both involve a somewhat random joining of gene segments to generate the complete TCR chain).

• Similarly, generation of the TCR gamma chain involves VJ recombination, whereas generation of the TCR delta chain occurs by V(D)J 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 N- and P- nucleotide additions, which accounts for the great diversity in specificity of the T cell receptor for processed antigen.

The TCR Complex

The T-cell receptor complex with TCR-α and TCR-β chains, CD3 and ζ-chain accessory molecules and the co-receptor CD4

The transmembrane region of the TCR is composed of positively charged amino acids.

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 the ζ-chain.

These accessory molecules have negatively charged 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

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 exclusively binds the 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.

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 mechanism by which a T-cell elicits this response upon contact with its unique antigen is termed T-cell activation. There are a myriad of molecules involved in the complex biochemical process by which this occurs which, in a wider context, is generally 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 largely utilise the SRC family of kinases in transmembrane signalling to phosphorylate tyrosines that are part of immunoreceptor tyrosine/based activation motifs (ITAM) ^[2].

Early signally 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

References

1. ^ Kieke, Michele C.; Shusta, Eric V.; Teyton, Luc; Wittrup, K. Dane; Kranz, David M., "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 
2. ^ 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. 

3. Janeway CA, Jr. et al. (2005). Immunobiology (6th ed. ed.). Garland Science. ISBN 0-443-07310-4.  4. Abbas AK and Lichtman AH (2003). Cellular and Molecular Immunology (5th ed. ed.). Saunders, Philadelphia. ISBN 0-7216-0008-5. 

External links

• UMich Orientation of Proteins in Membranes protein/pdbid-2hac - Zeta-zeta dimer of T cell receptor
• MeSH T-Cell+Receptor
• T-cell Group - Cardiff University

See also

• T cell
• Co-stimulation