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

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6 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
Pages (from-to)5245 - 5256
Number of pages12
JournalJournal of Immunology
Volume192
Issue number11
DOIs
Publication statusPublished - 2014

Cite this

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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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.",
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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; Perlman, Stanley.

In: Journal of Immunology, Vol. 192, No. 11, 2014, p. 5245 - 5256.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes

AU - Trujillo, Jonathan A

AU - Gras, Stephanie

AU - Twist, Kelly-Anne

AU - Croft, Nathan P

AU - Channappanavar, Rudragouda

AU - Rossjohn, Jamie

AU - Purcell, Anthony W

AU - Perlman, Stanley

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.jimmunol.org/content/192/11/5245.full.pdf+html

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DO - 10.4049/jimmunol.1400111

M3 - Article

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EP - 5256

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

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ER -