TCR docking

What are the physical properties of T-cell receptors (TCRs) that can account for their inherent cross-reactivity with many different peptide–MHC combinations? Mark Davis' group have analysed the residues that are involved in initial binding and in stable interactions between TCRs and peptide–MHC complexes. The results, reported in Nature, indicate that TCR binding is a two-step process, in which initial docking on the MHC molecule is essentially a peptide-independent process.

The TCR molecule is a dimer composed of an α- and a β-chain, each of which consists of constant and variable immunoglobulin-like domains. The regions within the variable domains that comprise the peptide–MHC-binding interface are known as the complementarity-determining regions (CDRs). CDR1 and CDR2 seem to be positioned over the MHC molecule, whereas CDR3 seems to be positioned over the peptide.

Using the well-characterized TCR 2B4, which interacts with the moth cytochrome C (MCC)–IE^k peptide–MHC complex, Wu and colleagues analysed the contribution of individual residues in the MCC–IE^k complex to TCR binding by alanine-scanning mutagenesis and assessed binding affinity using surface plasmon resonance. Mutagenesis of the TCR-contact residues in MCC markedly disrupted binding, which indicates that peptide residues are important for the stable interaction of TCR and peptide–MHC.

Next, the authors analysed the contribution of individual residues in the MCC–IE^k complex during the initation phase of the interaction. In this phase, residues in the MHC helices contributed most to the TCR interaction.

These data indicate that TCR interactions with peptide–MHC complexes occur by a two-step process. First, the CDR1 and CDR2 loops of the TCR chains dock on the MHC helices, then an induced-fit mechanism allows CDR3 to interact specifically with the peptide in the MHC groove.