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

Jonathan A. Trujillo, Stephanie Gras, Kelly Anne Twist, Nathan P. Croft, Rudragouda Channappanavar, Jamie Rossjohn, Anthony W. Purcell, Stanley Perlman

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5245-5256
Number of pages12
JournalJournal of Immunology
Volume192
Issue number11
DOIs
StatePublished - Jun 1 2014
Externally publishedYes

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T-Lymphocyte Epitopes
Antiviral Agents
Epitopes
Immunity
T-Lymphocytes
Peptides
Coronavirus
Half-Life
Hot Temperature

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

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.; Perlman, Stanley.

In: Journal of Immunology, Vol. 192, No. 11, 01.06.2014, p. 5245-5256.

Research output: Contribution to journalArticle

Trujillo, Jonathan A. ; Gras, Stephanie ; Twist, Kelly Anne ; Croft, Nathan P. ; Channappanavar, Rudragouda ; Rossjohn, Jamie ; Purcell, Anthony W. ; Perlman, Stanley. / Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes. In: Journal of Immunology. 2014 ; Vol. 192, No. 11. pp. 5245-5256.
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