Structural engineering of pMHC reagents for T cell vaccines and diagnostics |
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Authors: | Mitaksov Vesselin Truscott Steven M Lybarger Lonnie Connolly Janet M Hansen Ted H Fremont Daved H |
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Institution: | Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. |
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Abstract: | MHC class I peptide complexes (pMHC) are routinely used to enumerate T cell populations and are currently being evaluated as vaccines to tumors and specific pathogens. Herein, we describe the structures of three generations of single-chain pMHC progressively designed for the optimal presentation of covalently associated epitopes. Our ultimate design employs a versatile disulfide trap between an invariant MHC residue and a short C-terminal peptide extension. This general strategy is nondisruptive of native pMHC conformation and T cell receptor engagement. Indeed, cell-surface-expressed MHC complexes with disulfide-trapped epitopes are refractory to peptide exchange, suggesting they will make safe and effective vaccines. Furthermore, we find that disulfide-trap stabilized, recombinant pMHC reagents reliably detect polyclonal CD8 T cell populations as proficiently as conventional reagents and are thus well suited to monitor or modulate immune responses during pathogenesis. |
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