T-Cell Receptor Cognate Target Prediction Based on Paired α and β Chain Sequence and Structural CDR Loop Similarities.

Esteban Lanzarotti,Paolo Marcatili,Morten Nielsen

doi:10.3389/fimmu.2019.02080

Abstract

T-cell receptors (TCR) mediate immune responses recognizing peptides in complex with major histocompatibility complexes (pMHC) displayed on the surface of cells. Resolving the challenge of predicting the cognate pMHC target of a TCR would benefit many applications in the field of immunology, including vaccine design/discovery and the development of immunotherapies. Here, we developed a model for prediction of TCR targets based on similarity to a database of TCRs with known targets. Benchmarking the model on a large set of TCRs with known target, we demonstrated how the predictive performance is increased (i) by focusing on CDRs rather than the full length TCR protein sequences, (ii) by incorporating information from paired α and β chains, and (iii) integrating information for all 6 CDR loops rather than just CDR3. Finally, we show how integration of the structure of CDR loops, as obtained through homology modeling, boosts the predictive power of the model, in particular in situations where no high-similarity TCRs are available for the query. These findings demonstrate that TCRs that bind to the same target also share, to a very high degree, sequence, and structural features. This observation has profound impact for future development of prediction models for TCR-pMHC interactions and for the use of such models for the rational design of T cell based therapies.

Highlights

A central checkpoint to unleashing a cellular immune response is the recognition of peptides presented by major histocompatibility complexes by T cell receptors (TCRs)
We describe a framework to predict the peptideMHC binding target of a TCR query based on inference from TCRs with known peptides in complex with major histocompatibility complexes (pMHC) binding preference (Figure 1A)
A query TCR is scored against a database of TCRs with known binding preference, and the pMHC target is inferred from the top-scoring hit

Summary

Introduction

A central checkpoint to unleashing a cellular immune response is the recognition of peptides presented by major histocompatibility complexes (pMHCs) by T cell receptors (TCRs). During this selection, T cells with TCRs that either cannot bind pMHCs (negative selection) or bind MHC molecules presenting self-peptides (positive selection) are removed. T cells with TCRs that either cannot bind pMHCs (negative selection) or bind MHC molecules presenting self-peptides (positive selection) are removed This process results in a repertoire of T cells with highly specific and selective TCRs, and it is estimated that each TCR can only bind a few thousand [1, 2] distinct pMHC complexes (of a total of more than 206 possibilities, assuming up to 3 MHC anchor positions). Structural studies from the last 30 years have shown that CDR3 loops usually present the most discriminative interactions with peptides, CDR2 loops interact mainly with the MHC and CDR1 loops tend to present soft interactions with both peptide and MHC [3,4,5]

Methods

Results

Conclusion