The two-faced T cell epitope. The ternary MHC: peptide epitope: TCR complex drives the class II immune response (structure from pdb id 1fyt; rendered with PyMol (Schrödinger, LLC)). Some of the epitope side-chains (blue, spacefill) interact with the MHC (green, cartoon), while others interact with the TCR (orange, cartoon). A TCR may recognize many peptides that have similar TCR-facing sequences but different MHC-facing sequences, as long as the peptide still binds the same MHC. We develop an integrated scoring mechanism that accounts for both aspects of immune recognition, combining the EpiMatrix epitope predictor (to identify peptides that are good MHC binders) with an assessment of cross-reactivity with human genome (to identify peptides that are unlike self and thus more likely to be recognized by TCR from effector T cells).