What Does the Shape Space of T Cell Epitopes Look Like?

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• The shape space model traditionally describes antibody-antigen interactions and informs antigenic maps for viral evolution.
• This concept is now extended to T cell receptors (TCRs) and their recognition of peptide-MHC complexes (pMHCs).

Purpose of the Study:

• To apply the shape space concept to TCR-pMHC interactions, integrating principles from statistical physics and computer science.
• To propose a model where TCR-pMHC binding involves multiple structural constraints, leading to disjointed regions in shape space.

Main Methods:

• Reviewing the history and theoretical underpinnings of shape space, energy landscapes, and complexity theory.
• Developing a computational model for TCR-pMHC binding based on structural constraints.
• Analyzing published mutagenesis assay data for TCR-pMHC interactions.

Main Results:

• The proposed model implies that pMHCs recognized by a single TCR can occupy multiple, non-convex regions within shape space.
• Predictions include that minor pMHC structural alterations can drastically affect immunogenicity.
• Published data partially support the idea that TCRs can recognize pMHCs with significantly different structures.

Conclusions:

• A multispecific and non-convex T cell epitope shape space has significant implications for predicting immune responses.
• This framework is relevant for applications in cancer immunotherapy and understanding immune recognition.