Structure and Function of T Cell Receptor

The T cell receptor (TCR) is an antigen receptor molecule on the surface of T cells, responsible for the recognition of antigen presented to T cells by MHC molecules leading potentially to the activation of the T cell and an immune response to the antigen. The T cell receptor is a heterodimer consisting of two transmembrane glycoprotein chains, the α and β chains (there are also a small proportion of γδ chains) each with two domains, which are linked by a disulphide bond.

The TCR bears some structural similarity to the Fab fragment of an antibody molecule. The α and β chains each posses a constant (C) domain proximal to the cell membrane and a variable (V) domain distal from the membrane. This gives a Vα and Cα domain for the α chain and a Vβ and Cβ domain for the β chain. The variable and constant domains of the α chain dimerise with the variable and constant domains of the β chain. All domains adopt the classical immunoglobulin fold with two anti-parallel β-sheets adopting a Greek key motif held together into a ‘sandwich’ by a disulphide bond. The Cα domain does differ a little in having part of the β sheet replaced by loosely packed strands and a short segment of α helix. Like the variable region of the Fab fragment of antibodies, the variability of amino acids in the V region of the TCR is not evenly distributed throughout the sequence but is concentrated into hypervariable regions which code for the hypervariable loops. These are brought together by the α and β chain at the tip of the TCR to form the Complementarity Determining Regions (CDRs) which make contact with the MHC. The alignment of the TCR CDRs differs slightly from those of antibody molecules. The Vα CDR2 loop for instance is oriented roughly at 90 degrees for the equivalent antibody CDR. The Vβ domain includes a fourth hypervariable region which does not have an equivalent in antibodies.

The short cytoplasmic tail of the TCR means it cannot directly signal when it binds to a peptide-MHC complex. Instead the TCR is associated on the cell membrane with a group of non polymorphic signalling molecules collectively called CD3 which transmit an intracellular signal when the TCR binds to a peptide-MHC complex. CD3 is made up of one γ and δ and two ε molecules which all have in their extracellular domains some limited sequence homology to the immunoglobulin domain. These molecules have small cytoplasmic domains and transmembrane domains with negatively charged residues. In the membrane, these negatively charged residues form salt bridges with the positively charged residues in the transmembrane region of the TCR. The TCR-CD3 receptor complex is completed by two other invariant proteins ζ and η which form dimmers linked by disulphide bonds. At the T cell surface therefore, the TCR-CD3 complex is expressed as an αβ (or γδ) heterodimer, in association with CD3γε and CD3δε dimmers with an intracellular ζζ homodimers or a ζη heterodimer.

Generation of T Cell Receptor Diversity

T cell gene rearrangement takes place in the thymus. The mechanism used to generate T cell diversity is essentially the same as that used for the generation of B cell diversity but without the somatic hypermutation on activation.

The T cell receptor is made up of α and β chains. The α chain is coded for by a set of V gene segments (Vα) and a set of joining or J gene segments (Jα). The β chain variable domain is coded for by a set of V gene segments (Vβ), a set of diversity or D gene segments (Dβ) and a set of J gene segments (Jβ).

The somatic recombination process of the α chain involves the random selection of a Vα gene segment which is then joined to a randomly selected Jα gene segment. This is catalysed by recombination activation genes (RAGs). Vα genes are prevented from accidentally joining to other Vα gene segments by the use of recombination signalling sequences (RSS) which consist of a heptamer, a 12 or 23 nucleotide spacer and a nonamer. This is the 12/23 rule and it prevents gene segments with a 12 nucleotide spacer being joined to other 12 spacer segments and gene segments with a 23 nucleotide spacer being joined to other 23 spacer segments. This same process prevents J, D and Vβ gene segments from self joining. The joining process is not precise and introduces further Junctional diversification.

The variable β chain is created by a randomly selected Dβ gene segment joining to a randomly selected Jβ segment and then the combination joining to a randomly selected Vβ gene segment. Junctional diversity also is introduced during these joins.

Diversity is concentrated in the CDR3 loop, contributed to by the joining of the β chain DJ gene segments.