Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

Abstract

T cell specificity emerges from a myriad of processes, ranging from the biological pathways that control T cell signaling to the structural and physical mechanisms that influence how TCRs bind antigen/MHC. Of these processes, the binding specificity of the TCR is a key component. However, TCR specificity is enigmatic: TCRs are at once specific but also cross-reactive. Although long-appreciated, this duality continues to puzzle immunologists and has implications for the development of TCR-based therapeutics. Here we review TCR specificity, emphasizing results that have emerged from structural and physical studies of TCR binding. We show how the TCR specificity/cross-reactivity duality can be rationalized from structural and biophysical principles. There is excellent agreement between predictions from these principles and classic predictions about the scope of TCR cross-reactivity. We demonstrate how these same principles can also explain amino acid preferences in immunogenic epitopes and highlight opportunities for structural considerations in predictive immunology.

Epstein Barr virus epitope/MHC interaction combined with convergent recombination drive selection of diverse T cell receptor α and β repertoires

“…Enrichment for certain characteristics would suggest that these features are important for pMHC interaction. (11, 29, 47–50).…”

Optimizing T‐cell receptor avidity with somatic hypermutation

“…However, in silico predictions are not enough to ensure that there will be no cross‐reactivity, as cross‐reactivity can be toward unrelated peptides and difficult to predict . Therefore, the true test of dangerous cross‐reactivity is in vivo .…”

Peptide-binding groove contraction linked to the lack of T-cell response: Using complex structure and energy to identify neoantigens

“…Given the success of the hardware-to-software strategy for the in silico folding of fast-folding proteins, the results of the present work, and the anticipation of quantum supremacy in five years or sooner, we suggest that the hardware-to-software strategy can be combined with some recent quantum computing techniques [53][54][55] to develop an advanced atom-based method for neoantigen identification. This method could reasonably account for cross-reactive epitopes [56] and use the energy and structure of a peptide•HLA•TCR complex to evaluate the propensity of the ternary complex for binding with CD4/CD8. Such a method may help overcome a considerable hurdle of using the patient tumor DNA information to develop PPVs for personalized cancer immunotherapy.…”