Structural engineering of pMHC reagents for T cell vaccines and diagnostics.
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.
Mitaksov
Vesselin
V
Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Truscott
Steven M
SM
Lybarger
Lonnie
L
Connolly
Janet M
JM
Hansen
Ted H
TH
Fremont
Daved H
DH
D000818:Animals; D018360:Crystallography, X-Ray; D003933:Diagnosis; D000939:Epitopes / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014612:Vaccines / Q000737:chemistry* / Q000276:immunology
D000939:Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014612:Vaccines
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