Loss of T Cell Antigen Recognition Arising from Changes in Peptide and Major Histocompatibility Complex Protein Flexibility

Abstract

Background: Modification of the MART-1 27-35 tumor antigen to improve MHC binding severely curtails immunogenicity with minimal structural alterations. Results: Modification enhances the flexibility of the peptide and MHC. Conclusion: Dynamical consequences of peptide modification contribute to the loss in antigenicity. Significance: Potential dynamical consequences should be considered in the design of peptide-based vaccines and may underlie aspects of T cell specificity.

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

“…30–31 Such modifications have in some cases unexpectedly altered peptide motion. 2,4 peptide conformation, 20 and T cell recognition, 32 and our findings reveal these effects can occur via through-peptide and through-protein mechanisms. Finally, our results suggest a link between peptide rigidity and hydrophobicity, two previously established determinants of peptide immunogenicity.…”

“…One such property is the rapid motion of peptides within MHC binding grooves. For example, enhanced conformational sampling of a modified tumor antigen led to the loss of immunogenicity and the failure of a vaccine candidate, 4 and the immunogenicity of cancer neo-antigens has been positively correlated with peptide rigidity. 5 Although useful in isolated cases or with small sets of peptides, molecular dynamics simulations are prohibitive for large-scale prediction efforts, such as those needed for work with cancer neo-antigens or pathogens with large or unstable viruses.…”

“…5 In another study, molecular dynamics simulations were used to show that a peptide-based vaccine candidate’s poor immunogenicity was associated with its more rapid mobility in the MHC binding groove. 4 …”

A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces

“…However, although the TCR-pMHC structural database has grown significantly in recent years, wide-scale application of structure-guided TCR design is hindered by several complexities. These include the complex architecture of the TCR-pMHC interface Rossjohn et al, 2015), as well as the varying degrees of diversity and molecular flexibility in both receptor and ligand Insaidoo et al, 2011;Scott et al, 2011). We demonstrated the limited applicability of current TCR design approaches here by showing that our prior approach used to successfully engineer the clinically relevant DMF5 TCR performed poorly when applied to the unrelated B7 TCR.…”

“…Accounting for flexibility is an important aspect of our improved framework, as varying degrees of CDR loop, MHC and peptide flexibility is a characteristic feature of TCRs and pMHC complexes Insaidoo et al, 2011;Scott et al, 2011). As with other efforts in protein design, we relied on MD simulations to incorporate flexibility.…”