Going Pro to enhance T-cell immunogenicity: easy as π?

Abstract

MHC class I molecules bind intracellular oligopeptides and present them on the cell surface for CD8(+) T-cell activation and recognition. Strong peptide/MHC class I (pMHC) interactions typically induce the best CD8(+) T-cell responses; however, many immunotherapeutic tumor-specific peptides bind MHC with low affinity. To overcome this, immunologists can carefully alter peptides for enhanced MHC affinity but often at the cost of decreased T-cell recognition. A new report published in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43:3051-3060] shows that the substitution of proline at the third residue (p3P) of a common tumor peptide increases pMHC affinity and complex stability while enhancing T-cell receptor recognition. X-ray crystallography indicates that stability is generated through newly introduced CH-π bonding between p3P and a conserved residue (Y159) in the MHC heavy chain. This finding highlights a previously unappreciated role for CH-π bonding in MHC peptide binding, and importantly, arms immunologists with a novel and possibly general approach for increasing pMHC stability without compromising T-cell recognition.

Keywords: Altered peptide ligand; MHC class I; Peptide; Tumor-associated Ag.

Figure 1

“One π to Rule Them All”. Residues at peptide positions 5 and 9 interact with deep pockets in the Db binding groove, and have a large effect on peptide binding affinity. Uchtenhagen et al. show that position 3 can also make a large contribution to binding. Pro not only increases Db binding affinity of the 9-mer peptide, but also increases T-cell activation. This effect is due to pi-binding of the proline to Tyr at position 159 of Db. 159 residue is highly conserved among class I molecules, raising the possibility that substituting Pro at position 3 will be a more general strategy for increasing peptide immunogenicity.