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. The binding between TCR and antigen is of relatively low affinity and is degenerate: that is, many TCR recognize the same antigen and many antigen 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.

Structural characteristics of the TCR
TCR, which is anchored in the cell membrane, consists of two halves, which form a pair (or dimer) of protein chains. The halves are called the alpha (α) and beta (β) fragments (in γ/δ T cells, the halves are gamma (γ) and delta (δ) fragments). Each fragment is divided in turn into a constant (C) and variable (V) region. The constant region has an end that is anchored in the cell membrane. The variable region faces outward and binds to the HLA molecule and the antigen it presents. On the α chain, the variable region is called Vα and the constant region is called Cα; on the β chain, they are called Vβ and Cβ, respectively.

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 α- and β-chains and in the β-chain framework region that is thought to be in proximity to the CD3 signal-transduction complex. 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
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).


 * Likewise, 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 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 either a ζ2 complex or a ζ/η complex.

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 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.

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 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).

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