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However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T\u00a0cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in\u00a0the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on\u00a0cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.","bibjson":{"author":[{"initials":"LM","lastname":"Hellman","name":"Hellman LM"},{"initials":"KC","lastname":"Foley","name":"Foley KC"},{"initials":"NK","lastname":"Singh","name":"Singh NK"},{"initials":"JA","lastname":"Alonso","name":"Alonso JA"},{"initials":"TP","lastname":"Riley","name":"Riley TP"},{"initials":"JR","lastname":"Devlin","name":"Devlin JR"},{"initials":"CM","lastname":"Ayres","name":"Ayres CM"},{"initials":"GLJ","lastname":"Keller","name":"Keller GLJ"},{"initials":"Y","lastname":"Zhang","name":"Zhang Y"},{"initials":"CW","lastname":"Vander Kooi","name":"Vander Kooi CW"},{"initials":"MI","lastname":"Nishimura","name":"Nishimura MI"},{"initials":"BM","lastname":"Baker","name":"Baker BM"}],"identifier":[{"id":"10.1016/j.ymthe.2018.12.010","type":"doi"},{"id":"30617019","type":"pubmed"}],"issue":["2"],"journal":{"iso_abbreviation":"Mol. 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