Structural basis for ineffective T‐cell responses to MHC anchor residue‐improved “heteroclitic” peptides

Abstract

MHC anchor residue-modified “heteroclitic” peptides have been used in many cancer vaccine trials and often induce greater immune responses than the wild-type peptide. The best-studied system to date is the decamer MART-1/Melan-A26–35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor-expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a TCR in complex with HLA-A*0201-EAAGIGILTV peptide and compared it with its heteroclitic counterpart, HLA-A*0201-ELAGIGILTV. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to “pull” the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes that differ by only a single MHC anchor residue and demonstrate how weak MHC anchoring can enable an induced-fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation.

Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase

“…Our structural analysis demonstrated that, again, even single peptide substitutions outside of the main interaction interface could have a substantial impact on TCR binding affinity and T-cell antigen potency, consistent with our previous data (9, 15, 16). These observations add further evidence to our recent findings (19, 31–34) that peptide presentation by MHCI can be dynamic and difficult to predict.…”

TCR‐induced alteration of primary MHC peptide anchor residue

“…A) and α24β17 TCRs in complex with A2‐AAG was similar to the MEL5‐A2‐EAA complex. This was reflected by similar crossing angles of 48° and 42.3° and buried surface areas (BSAs) of ≈2200 and ≈2600 Å for MEL5 and α24β17 TCRs, respectively, in complex with A2‐AAG (Table ), compared to a crossing angle of 46.9° and BSA of 2366 Å for MEL5‐A2‐EAA .…”

Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide–MHC complexes

“…In principle, the analysis could detect additional complexities, such as partial/multi-step dissociation, register-shifting, or multi-mode binding. Partial dissociation has been implicated in peptide immunogenicity (Duan et al, 2014) and in facilitating optimal T cell receptor binding (Madura et al, 2015). Register shifting or multi-mode binding has been seen in peptides that bind both class I and class II MHC proteins (Borbulevych et al, 2007; Landais et al, 2009; Günther et al, 2010).…”