Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes

• Published in: The Journal of immunology (1950) 2014-06, Vol.192 (11), p.5245-5256
• Main Authors: Trujillo, Jonathan A, Gras, Stephanie, Twist, Kelly-Anne, Croft, Nathan P, Channappanavar, Rudragouda, Rossjohn, Jamie, Purcell, Anthony W, Perlman, Stanley
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Antigens, Viral - genetics; Antigens, Viral - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Coronavirus - genetics; Coronavirus - immunology; Coronavirus Infections - genetics; Coronavirus Infections - immunology; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; HeLa Cells; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Humans; Mice; Mutation, Missense; Peptides - genetics; Peptides - immunology; Viral Proteins - genetics; Viral Proteins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400111

Peptides 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.