Abstract
The physical interaction between the T cell receptor (TCR) and its cognate antigen causes T cells to activate and participate in the immune response. Understanding this physical interaction is important in predicting TCR binding to a target epitope, as well as potential cross-reactivity. Here, we propose a way of collecting informative features of the binding interface from homology models of T cell receptor-peptide-major histocompatibility complex (TCR-pMHC) complexes. The information collected from these structures is sufficient to discriminate binding from non-binding TCR-pMHC pairs in multiple independent datasets. The classifier is limited by the number of crystal structures available for the homology modelling and by the size of the training set. However, the classifier shows comparable performance to sequence-based classifiers requiring much larger training sets.
Highlights
T cells are key players of adaptive immunity
The recognition occurs via the T cell receptor (TCR), which is composed of two chains, both of which are generated by a process of random recombination and selection
CDR3 is the most variable as it is found at the junction of V(D)J recombination, and it can incorporate a number of non-template insertion and deletion events, whilst CDR1 and CDR2 depend on the V gene selected in the recombination process and have a lower number of possible sequences
Summary
T cells are key players of adaptive immunity They are activated by the recognition of a cognate peptide, a short stretch of amino acids which is displayed on a major histocompatibility complex molecule (MHC, pMHC when bound to peptide). A number of TCR-pMHC complexes have been crystallised and their structures solved and they are collected in the Structural T-Cell Receptor Database (STCRDab, Leem et al, 2018). They have given us deeper understanding of TCR-pMHC interactions and how these are impacted by mutations, and how structure and function are related. Examples include how cross-reactivity between bacterial and self antigens can drive disease (Petersen et al, 2020), how binding mode can TCR-pMHC Binding From Homology Models give different specificity profiles to TCRs binding the same peptide (Coles et al, 2020), and how binding orientation is determined by how the peptide is presented by the MHC (Singh et al, 2020)
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