Abstract

BackgroundImmune recognition of foreign proteins by T cells hinges on the formation of a ternary complex sandwiching a constituent peptide of the protein between a major histocompatibility complex (MHC) molecule and a T cell receptor (TCR). Viruses have evolved means of "camouflaging" themselves, avoiding immune recognition by reducing the MHC and/or TCR binding of their constituent peptides. Computer-driven T cell epitope mapping tools have been used to evaluate the degree to which particular viruses have used this means of avoiding immune response, but most such analyses focus on MHC-facing 'agretopes'. Here we set out a new means of evaluating the TCR faces of viral peptides in addition to their agretopes, integrating evaluations of both sides of the ternary complex in a single analysis.MethodsThis paper develops what we call the Janus Immunogenicity Score (JIS), bringing together a well-established method for predicting MHC binding, with a novel assessment of the potential for TCR binding based on similarity with self. Intuitively, both good MHC binding and poor self-similarity are required for high immunogenicity (i.e., a robust T effector response).ResultsFocusing on the class II antigen-processing pathway, we show that the JIS of T effector epitopes and null or regulatory epitopes deposited in a large database of epitopes (Immune Epitope Database) are significantly different. We then show that different types of viruses display significantly different patterns of scores over their constituent peptides, with viruses causing chronic infection (Epstein-Barr and cytomegalovirus) strongly shifted to lower scores relative to those causing acute infection (Ebola and Marburg). Similarly we find distinct patterns among influenza proteins in H1N1 (a strain against which human populations rapidly developed immunity) and H5N1 and H7N9 (highly pathogenic avian flu strains, with significantly greater case mortality rates).ConclusionThe Janus Immunogenicity Score, which integrates MHC binding and TCR cross-reactivity, provides a new tool for studying immunogenicity of pathogens and may improve the selection and optimization of antigenic elements for vaccine design.

Highlights

  • Immune recognition of foreign proteins by T cells hinges on the formation of a ternary complex sandwiching a constituent peptide of the protein between a major histocompatibility complex (MHC) molecule and a T cell receptor (TCR)

  • We conclude that Janus Immunogenicity Score (JIS) does distinguish immunogenicity risk, separating T cell epitopes that induce regulatory cytokines or no detected immune response from those that are associated with T effector cytokines, for this dataset

  • Commensal viruses appear to avoid immune response by (1) reducing their epitope content and (2) adopting more human-like TCR faces among the remaining epitopes, when compared to acute viruses and plant-virus controls

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Summary

Introduction

Immune recognition of foreign proteins by T cells hinges on the formation of a ternary complex sandwiching a constituent peptide of the protein between a major histocompatibility complex (MHC) molecule and a T cell receptor (TCR). T helper (MHC class II-restricted) epitopes within viral and bacterial proteins are a necessary component of immune protection against these pathogens since the presentation of a T-cell epitope in the context of MHC Class II molecules is essential for a B-cell to be stimulated and produce high-affinity and high-titer antibodies. Since this interaction is the one that initiates a specific immune response against the pathogen, one means by which pathogens evade immune response is to present proteins with lower immunogenic potential [3].

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