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

Trujillo, Jonathan A., Gras, Stephanie, Twist, Kelly-Anne, Croft, Nathan P., Channappanavar, Rudragouda, Rossjohn, Jamie, Purcell, Anthony W. and Perlman, Stanley 2014. Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes. The Journal of Immunology 192 (11) , pp. 5245-5256. 10.4049/jimmunol.1400111

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
Publisher: American Association of Immunologists
ISSN: 0022-1767
Date of Acceptance: 1 April 2014
Last Modified: 25 Apr 2019 16:04
URI: http://orca.cf.ac.uk/id/eprint/79573

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