Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner

Abstract

Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. Increasing evidence, however, indicates that T cell receptors (TCRs) can perceive such anchor-modified peptides differently than wild-type (WT) peptides, although the scope of discrimination is unclear. We show here that even modifications at primary anchors that have no discernible structural impact can lead to substantially stronger or weaker T cell recognition depending on the TCR. Surprisingly, the effect of peptide anchor modification can be sensed by a TCR at regions distant from the site of modification, indicating a through-protein mechanism in which the anchor residue serves as an allosteric modulator for TCR binding. Our findings emphasize caution in the use and interpretation of results from anchor-modified peptides and have implications for how anchor modifications are accounted for in other circumstances, such as predicting the immunogenicity of tumor neoantigens. Our data also highlight an important need to better understand the highly tunable dynamic nature of class I MHC proteins and the impact this has on various forms of immune recognition.

Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM

“…Our structural analysis of MAGEA4 and MAGEA8 pMHCs showed how a conservative valine to leucine substitution at anchor residue position 2 can allosterically impact the conformation of solvent-exposed peptide residues contacted by TCR, thus affecting recognition. This finding is consequential for the development of cancer vaccines that use mutated anchor residues (often introducing leucine at position 2) to improve stability of the peptide in the HLA groove 41,42 , and corroborates previous studies showing that anchor residue modification can impact TCR recognition [43][44][45][46] . Our study therefore highlights the importance of obtaining structural data to understand the effects of subtle sequence variations on peptide presentation by MHC.…”

Conserved Biophysical Compatibility Among the Highly Variable Germline-Encoded Regions Shapes TCR-MHC Interactions

“…However, these codons as currently posited suggest the existence of multiple rigid docking modes, consistent with their ideation deriving from solved crystal structures. The results of our analyses instead suggest a broader, dynamic interpretation of the TCR-pMHC interface [55][56][57][58][59], with the TCR CDR loops sampling local regions of increased interaction potential on the MHC surface, utilizing a more opportunistic approach to binding.…”

Physicochemical Heuristics for Identifying High Fidelity, Near-Native Structural Models of Peptide/MHC Complexes

“…However, while speed and accessibility have improved over the years, improvements in peptide-MHC modeling accuracy have been modest. Accuracy is crucial in peptide-MHC modeling, as TCRs are highly sensitive to subtle perturbations, and small changes in peptide backbone or side chain positions can separate a strong agonist from an irrelevant peptide ( 15 , 76 , 77 ). Here, we explored methods to improve the accuracy of peptide-MHC structural modeling, focusing on nonamers presented by the human class I protein HLA-A*02:01.…”