Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for “Holes” in the T Cell Repertoire

Sune Frankild,Morten Nielsen,Rob J De Boer,Can Kesmir,Ole Lund,Linqi Zhang

doi:10.1371/journal.pone.0001831

Sune Frankild, Morten Nielsen + Show 4 more

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https://doi.org/10.1371/journal.pone.0001831

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Journal: PloS one	Publication Date: Mar 19, 2008
Citations: 139	License type: CC0 1.0

Affiliation: Technical University of Denmark, Utrecht University

Abstract

BackgroundCytotoxic T cell (CTL) cross-reactivity is believed to play a pivotal role in generating immune responses but the extent and mechanisms of CTL cross-reactivity remain largely unknown. Several studies suggest that CTL clones can recognize highly diverse peptides, some sharing no obvious sequence identity. The emerging realization in the field is that T cell receptors (TcR) recognize multiple distinct ligands.Principal FindingsFirst, we analyzed peptide scans of the HIV epitope SLFNTVATL (SFL9) and found that TCR specificity is position dependent and that biochemically similar amino acid substitutions do not drastically affect recognition. Inspired by this, we developed a general model of TCR peptide recognition using amino acid similarity matrices and found that such a model was able to predict the cross-reactivity of a diverse set of CTL epitopes. With this model, we were able to demonstrate that seemingly distinct T cell epitopes, i.e., ones with low sequence identity, are in fact more biochemically similar than expected. Additionally, an analysis of HIV immunogenicity data with our model showed that CTLs have the tendency to respond mostly to peptides that do not resemble self-antigens.ConclusionsT cell cross-reactivity can thus, to an extent greater than earlier appreciated, be explained by amino acid similarity. The results presented in this paper will help resolving some of the long-lasting discussions in the field of T cell cross-reactivity.

Highlights

Each T cell expresses thousands of T cell receptors (TCR) of a single specificity that allows inspection of peptide fragments bound by major histocompatibility complex molecules (MHC) on the surface of other cells
The results presented in this paper will help resolving some of the long-lasting discussions in the field of T cell cross-reactivity
Several studies suggest that T cells can recognize seemingly dissimilar epitopes, while other studies have established that substitutions affect peptide recognition in a predictable and additive manner [9] suggesting that the majority of cross-reactive peptide:MHC complexes (pMHC) complexes share structural similarities

Summary

Introduction

Each T cell expresses thousands of T cell receptors (TCR) of a single specificity that allows inspection of peptide fragments bound by major histocompatibility complex molecules (MHC) on the surface of other cells. Several studies suggest that T cells can recognize seemingly dissimilar epitopes (for a summary see [6]), while other studies have established that substitutions affect peptide recognition in a predictable and additive manner [9] suggesting that the majority of cross-reactive pMHC complexes share structural similarities. We investigate a simple model of T cell crossreactivity and perform a large-scale analysis spanning both a broad set of experimental settings, heterogeneous pathogens, MHC molecules and T cell clones. We use this benchmark to investigate whether cross-reactivity is either generally predictable or mostly random. The emerging realization in the field is that T cell receptors (TcR) recognize multiple distinct ligands

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