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that bind poorly to MHC class I molecules often elicit low-functional avidity T cell responses. Peptide modification by altering the anchor residue facilitates increased binding affinity and may elicit T cells with increased functional avidity toward the native epitope (\"heteroclitic\"). This augmented MHC binding is likely to increase the half-life and surface density of the heteroclitic complex, but precisely how this enhanced T cell response occurs in vivo is not known. Furthermore, the ideal heteroclitic epitope will elicit T cell responses that completely cross-react with the native epitope, maximizing protection and minimizing undesirable off-target effects. Such epitopes have been difficult to identify. In this study, using mice infected with a murine coronavirus that encodes epitopes that elicit high (S510, CSLWNGPHL)- and low (S598, RCQIFANI)-functional avidity responses, we show that increased expression of peptide S598 but not S510 generated T cells with enhanced functional avidity. Thus, immune responses can be augmented toward T cell epitopes with low functional avidity by increasing Ag density. We also identified a heteroclitic epitope (RCVIFANI) that elicited a T cell response with nearly complete cross-reactivity with native epitope and demonstrated increased MHC/peptide abundance compared with native S598. Structural and thermal melt analyses indicated that the Q600V substitution enhanced stability of the peptide/MHC complex without greatly altering the antigenic surface, resulting in highly cross-reactive T cell responses. Our data highlight that increased peptide/MHC complex display contributes to heteroclitic epitope efficacy and describe parameters for maximizing immune responses that cross-react with the native epitope.","bibjson":{"author":[{"initials":"JA","lastname":"Trujillo","name":"Trujillo JA"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"KA","lastname":"Twist","name":"Twist KA"},{"initials":"NP","lastname":"Croft","name":"Croft NP"},{"initials":"R","lastname":"Channappanavar","name":"Channappanavar R"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"S","lastname":"Perlman","name":"Perlman S"}],"identifier":[{"id":"10.4049/jimmunol.1400111","type":"doi"},{"id":"24795457","type":"pubmed"}],"issue":["11"],"journal":{"iso_abbreviation":"J. 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