Interactions

MHC-CD4 interactions

The TCR-pMHC-CD4 complex structure resembles an arrow head with an MHC apex and a CD4 and TCR bound at opposing sides. The α2 β2 domains of MHCII form a binding site for CD4's distal D1 domain, the MHCII amino acids at the site of binding are conserved throughout human MHCII (Fig. 5). It has been discussed already that the binding strength at this binding cleft is increased by mutations of Gln40 for Tyr and Thr45 for Trp, these increase hydrophobic interactions. 

Angles: TCR – cell surface = 60°

            CD4 – cell surface = 70°

It has been suggested that MHCII may act as a dimer to cross link two TCRs and initiate T cell activation. This is based on a crystal structure of MHCII as a dimer and MHCII having been detected on the cell surface as a dimer. Using a univalent fluorescent probe of HLA-DR A and B, fluorescence measurements were taken to reveal HLA-DR heterodimers and dimer of dimers. This has however been argued against as the CD4 binding site on HLA-DR nearly coincides with the dimerization site.

MHC-TCR interactions

A crystal structure of TCR and MHCII was determined at a resolution of 3.2A (EL Reinherz et al, 1999). The MHC binding cleft contains residues that insert their amino terminals into the cleft that the TCR complementarity determining regions binds to (fig6). The TCR interacts with the MHC in a diagonal orientation, as seen in the ternary complex crystal structure (Fig. 5). The α chain variable region interacts with the N-terminus of the peptide bound to the MHCII and the β chain variable region interacting with the C terminus.  

Although generalizations for the interactions between pMHC-TCR can be made, the specific pitch and angle of binding will vary for every example. Generalizations for binding between the two can be made in this case with reference to two theories, both of which have counter arguments.

• Germline encoded hyper-variable domains (CDR1 and CDR2) have evolved with the MHC α-helices to develop specific interaction motifs to initiate binding. However, it has been found that evolutionary selection is not always responsible for these interactions.

• Positive selection eliminates all T cells with receptors that cannot bind to MHCs in such a way.

Figure 6: 

X-ray structure of interacting MHCII and TCR 

MHCII-staphylococcal enterotoxin B (SEB)–T cell receptor (TCR) complex 

(P.C Anastassios, R. Acharya, 2000)