Integrated assessment of predicted MHC binding and cross-conservation with self reveals patterns of viral camouflage

BACKGROUND: 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). 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. METHODS: This 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). RESULTS: Focusing 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). CONCLUSION: The 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.