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

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.

HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients

“…Indeed, recent analyses indicated that Epstein-Barr virus and cytomegalovirus contained fewer T cell epitopes and exhibited higher crossreactivity with the human genome than did either Ebola or Marburg virus [14]. Ebola and Marburg viruses, on the other hand, were composed of significantly fewer peptide sequences that were crossreactive with human and expressed a larger number of predicted T cell epitopes.…”

“…JanusMatrix, a new bioinformatics tool, interrogates a potential T cell epitope from both its HLA-binding and TcR-facing aspects, and assesses TcR cross-reactivity with T cell epitopes encoded by other genomes [13,14]. Those epitopes from two different genomic sources, e.g., HCV and human, that bind the same HLA molecules and present identical amino acids to the TcR are designated potentially cross-reactive, capable of stimulating the same TcR and triggering the same T cells to respond.…”

“…This peptide exhibited human homology when evaluated using GenBank Basic Local Alignment Search Tool (BLAST) [12]. Further analysis using a new bioinformatics tool, JanusMatrix [13,14], demonstrated that this HCV peptide cross-reacts with HLA matched peptide sequences located within hundreds of human proteins. Our data suggest that HCV_G1_p7_794 engages preexisting nT reg cells as a consequence of this homology, induces infectious tolerance and the expansion of an iT reg cell population, which contributes to suppression of effector T (eff) cell activity in cases of chronic HCV infection.…”

Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome

“…Homology to the human genome was recently discovered in some commensal viruses using the same tool, and was found to differ quite significantly from the level of homology to self for 'hit-and-run' viruses like Variola, Ebola, and Marburg. 64 In reality, TCRs are able to recognize their target epitopes by AA residue side-chain availability; this means that JanusMatrix cannot predict all putative cross-reactive epitopes derived from the human genome based on sequence similarity alone, however it can still help narrow down the set of epitopes that would be later tested experimentally to prove whether or not they trigger suppressive or autoimmune responses. 21 For our predicted HLA class I set, we stringently selected only the epitopes with zero cross-reactive hits in the human genome.…”

iVAX: An integrated toolkit for the selection and optimization of antigens and the design of epitope-driven vaccines

“…Recently, the collaborating groups at EpiVax and iCubed discovered epitopes that activate T regulatory cells (Tregs) in viral pathogens using the JanusMatrix tool. 24,[34][35][36] Epitope-driven vaccines designed using the iVAX toolkit have been tested using a number of new delivery methods that will also be reviewed below.…”