Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses

Alice Denton, Rob Wesselingh, Stephanie Gras, Carole Guillonneau, Matthew R Olson, Justine D Mintern, Weiguang Zeng, David C Jackson, Jamie Rossjohn, Philip D Hodgkin, Peter C Doherty, Stephen J Turner

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

High-avidity interactions between TCRs and peptide + class I MHC (pMHCI) epitopes drive CTL activation and expansion. Intriguing questions remain concerning the constraints determining optimal TCR/pMHCI binding. The present analysis uses the TCR transgenic OT-I model to assess how varying profiles of TCR/pMHCI avidity influence naive CTL proliferation and the acquisition of effector function following exposure to the cognate H-2K(b)/OVA(257-264) (SIINFEKL) epitope and to mutants provided as peptide or in engineered influenza A viruses. Stimulating naive OT-I CD8(+) T cells in vitro with SIINFEKL induced full CTL proliferation and differentiation that was largely independent of any need for costimulation. By contrast, in vitro activation with the low-affinity EIINFEKL or SIIGFEKL ligands depended on the provision of IL-2 and other costimulatory signals. Importantly, although they did generate potent endogenous responses, infection of mice with influenza A viruses expressing these same OVA(257) variants failed to induce the activation of adoptively transferred naive OT-I CTLps, an effect that was only partially overcome by priming with a lipopeptide vaccine. Subsequent structural and biophysical analysis of H2-K(b)OVA(257), H2-K(b)E1, and H2-K(b)G4 established that these variations introduce small changes at the pMHCI interface and decrease epitope stability in ways that would likely impact cell surface presentation and recognition. Overall, it seems that there is an activation threshold for naive CTLps, that minimal alterations in peptide sequence can have profound effects, and that the antigenic requirements for the in vitro and in vivo induction of CTL proliferation and effector function differ substantially.
Original languageEnglish
Pages (from-to)5733-5744
Number of pages12
JournalJournal of Immunology
Volume187
Issue number11
DOIs
Publication statusPublished - 2011

Cite this

Denton, Alice ; Wesselingh, Rob ; Gras, Stephanie ; Guillonneau, Carole ; Olson, Matthew R ; Mintern, Justine D ; Zeng, Weiguang ; Jackson, David C ; Rossjohn, Jamie ; Hodgkin, Philip D ; Doherty, Peter C ; Turner, Stephen J. / Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses. In: Journal of Immunology. 2011 ; Vol. 187, No. 11. pp. 5733-5744.
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title = "Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses",
abstract = "High-avidity interactions between TCRs and peptide + class I MHC (pMHCI) epitopes drive CTL activation and expansion. Intriguing questions remain concerning the constraints determining optimal TCR/pMHCI binding. The present analysis uses the TCR transgenic OT-I model to assess how varying profiles of TCR/pMHCI avidity influence naive CTL proliferation and the acquisition of effector function following exposure to the cognate H-2K(b)/OVA(257-264) (SIINFEKL) epitope and to mutants provided as peptide or in engineered influenza A viruses. Stimulating naive OT-I CD8(+) T cells in vitro with SIINFEKL induced full CTL proliferation and differentiation that was largely independent of any need for costimulation. By contrast, in vitro activation with the low-affinity EIINFEKL or SIIGFEKL ligands depended on the provision of IL-2 and other costimulatory signals. Importantly, although they did generate potent endogenous responses, infection of mice with influenza A viruses expressing these same OVA(257) variants failed to induce the activation of adoptively transferred naive OT-I CTLps, an effect that was only partially overcome by priming with a lipopeptide vaccine. Subsequent structural and biophysical analysis of H2-K(b)OVA(257), H2-K(b)E1, and H2-K(b)G4 established that these variations introduce small changes at the pMHCI interface and decrease epitope stability in ways that would likely impact cell surface presentation and recognition. Overall, it seems that there is an activation threshold for naive CTLps, that minimal alterations in peptide sequence can have profound effects, and that the antigenic requirements for the in vitro and in vivo induction of CTL proliferation and effector function differ substantially.",
author = "Alice Denton and Rob Wesselingh and Stephanie Gras and Carole Guillonneau and Olson, {Matthew R} and Mintern, {Justine D} and Weiguang Zeng and Jackson, {David C} and Jamie Rossjohn and Hodgkin, {Philip D} and Doherty, {Peter C} and Turner, {Stephen J}",
year = "2011",
doi = "10.4049/jimmunol.1003937",
language = "English",
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Denton, A, Wesselingh, R, Gras, S, Guillonneau, C, Olson, MR, Mintern, JD, Zeng, W, Jackson, DC, Rossjohn, J, Hodgkin, PD, Doherty, PC & Turner, SJ 2011, 'Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses', Journal of Immunology, vol. 187, no. 11, pp. 5733-5744. https://doi.org/10.4049/jimmunol.1003937

Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses. / Denton, Alice; Wesselingh, Rob; Gras, Stephanie; Guillonneau, Carole; Olson, Matthew R; Mintern, Justine D; Zeng, Weiguang; Jackson, David C; Rossjohn, Jamie; Hodgkin, Philip D; Doherty, Peter C; Turner, Stephen J.

In: Journal of Immunology, Vol. 187, No. 11, 2011, p. 5733-5744.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses

AU - Denton, Alice

AU - Wesselingh, Rob

AU - Gras, Stephanie

AU - Guillonneau, Carole

AU - Olson, Matthew R

AU - Mintern, Justine D

AU - Zeng, Weiguang

AU - Jackson, David C

AU - Rossjohn, Jamie

AU - Hodgkin, Philip D

AU - Doherty, Peter C

AU - Turner, Stephen J

PY - 2011

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N2 - High-avidity interactions between TCRs and peptide + class I MHC (pMHCI) epitopes drive CTL activation and expansion. Intriguing questions remain concerning the constraints determining optimal TCR/pMHCI binding. The present analysis uses the TCR transgenic OT-I model to assess how varying profiles of TCR/pMHCI avidity influence naive CTL proliferation and the acquisition of effector function following exposure to the cognate H-2K(b)/OVA(257-264) (SIINFEKL) epitope and to mutants provided as peptide or in engineered influenza A viruses. Stimulating naive OT-I CD8(+) T cells in vitro with SIINFEKL induced full CTL proliferation and differentiation that was largely independent of any need for costimulation. By contrast, in vitro activation with the low-affinity EIINFEKL or SIIGFEKL ligands depended on the provision of IL-2 and other costimulatory signals. Importantly, although they did generate potent endogenous responses, infection of mice with influenza A viruses expressing these same OVA(257) variants failed to induce the activation of adoptively transferred naive OT-I CTLps, an effect that was only partially overcome by priming with a lipopeptide vaccine. Subsequent structural and biophysical analysis of H2-K(b)OVA(257), H2-K(b)E1, and H2-K(b)G4 established that these variations introduce small changes at the pMHCI interface and decrease epitope stability in ways that would likely impact cell surface presentation and recognition. Overall, it seems that there is an activation threshold for naive CTLps, that minimal alterations in peptide sequence can have profound effects, and that the antigenic requirements for the in vitro and in vivo induction of CTL proliferation and effector function differ substantially.

AB - High-avidity interactions between TCRs and peptide + class I MHC (pMHCI) epitopes drive CTL activation and expansion. Intriguing questions remain concerning the constraints determining optimal TCR/pMHCI binding. The present analysis uses the TCR transgenic OT-I model to assess how varying profiles of TCR/pMHCI avidity influence naive CTL proliferation and the acquisition of effector function following exposure to the cognate H-2K(b)/OVA(257-264) (SIINFEKL) epitope and to mutants provided as peptide or in engineered influenza A viruses. Stimulating naive OT-I CD8(+) T cells in vitro with SIINFEKL induced full CTL proliferation and differentiation that was largely independent of any need for costimulation. By contrast, in vitro activation with the low-affinity EIINFEKL or SIIGFEKL ligands depended on the provision of IL-2 and other costimulatory signals. Importantly, although they did generate potent endogenous responses, infection of mice with influenza A viruses expressing these same OVA(257) variants failed to induce the activation of adoptively transferred naive OT-I CTLps, an effect that was only partially overcome by priming with a lipopeptide vaccine. Subsequent structural and biophysical analysis of H2-K(b)OVA(257), H2-K(b)E1, and H2-K(b)G4 established that these variations introduce small changes at the pMHCI interface and decrease epitope stability in ways that would likely impact cell surface presentation and recognition. Overall, it seems that there is an activation threshold for naive CTLps, that minimal alterations in peptide sequence can have profound effects, and that the antigenic requirements for the in vitro and in vivo induction of CTL proliferation and effector function differ substantially.

UR - http://www.jimmunol.org/content/187/11/5733.full.pdf+html

U2 - 10.4049/jimmunol.1003937

DO - 10.4049/jimmunol.1003937

M3 - Article

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JO - Journal of Immunology

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