The two-faced T cell epitope: examining the host-microbe interface with JanusMatrix (P4399)

Abstract

Abstract To explore the intersection of commensals, pathogens, and the human genome at the T cell epitope level, we leveraged the vast genomic sequence information available in databases of microorganisms to which humans are exposed. We developed the JanusMatrix immunoinformatic tool that identifies potentially cross-reactive T cell epitopes from both HLA binding and TCR-facing sides to allow comparison across large genome sequence databases including common human pathogens (HP), the human gut microbiome (HGM), the human genome (HG), and the human plasma proteome (HPP). Initial studies reveal different levels of HPP/HG, HGM, and HP cross-reactivity (XR) for known Treg and Teff epitopes. In Hand Foot Mouth Disease (HFMD), extensive XR with HGM seems to predict immunodominance; more limited XR with enteroviruses (e.g., polio) may protect against severe HFMD. For common Teff epitopes, HPP/HG XR is more limited than HGM XR. For Treg epitopes defined in HCV disease and for Tregitopes (De Groot et al, Blood, 2008), HPP/HG XR is more extensive. Overall, greater XR with HPP/HG compared to HGM seems to distinguish known Treg and Teff epitopes. While predicting all influences on immune responses may be impossible, the vast availability of human pathogen and commensal organism sequences now allows T cell epitope comparisons in these large datasets. Startling discoveries relevant to vaccine development and T cell response phenotype understanding are emerging as we apply this powerful technology.