Summary

We have discussed:

• The instability of the ternary complex and how the affinity of interactions was increased by mutagenesis.

• How a specific mutant was chosen by SPR.

• The process of crystallization and crystallography.

• The MHC-CD4, MHC-TCR and Ternary complex-CD3 interactions.

• The phosphorylation reactions downstream of the ternary complex.

• The methods used by the researchers.

And in conclusion all of this research led to the crystal structure of the TCR-pMHC-CD4 ternary complex being determined. This structure is shown in the short video below.

What to do next

• Having determind the structural interactions of the TCR-pMHCII-CD4 ternary complex, a further investigation into the cytotoxic T cell interactions with MHCI and the CD8 coreceptor could highlight the differences between the two systems and their outcomes. Similar random mutation methods to determine the crystal structure could be used.

• Identification of the CD4 and TCR binding sites on MHCII allows them to be utilized as targets for autoimmune disease therapies. Drugs could be developed specifically to interact with the MHCII in these sites to inhibit TCR/CD4 binding. However, as  every MHCII binds a unique TCR as a result of antigen peptide specificity generalizations of these sites cannot be made.

References:

Reinherz, E et al. "The crystal structure of a T cell receptor in complex with peptide and MHC class II." 1999.

Papageorgiou, A. et al. "Microbial superantigens: from structure to function." 2000

Yin, Y. et al. "Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection" 2011

Hsu, S. et al. "Atomic insight into the CD4 binding-induced conformational changes in HIV-1 gp120." 2004

Au-Yeung, Byron B., et al. “The structure, regulation, and function of ZAP-70.” Immunological Reviews, 2009: 41-57