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Article: Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold
Title | Protective efficacy of cross-reactive CD8<sup>+</sup> T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold |
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Authors | |
Issue Date | 2010 |
Citation | PLoS Pathogens, 2010, v. 6, n. 8, p. 23-24 How to Cite? |
Abstract | Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. Pre- existing CD8+ T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP336-374 peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross-reactive T cell responses. The engineered virus induced a diminished CD8+ T cell response and selected a narrowed T cell receptor (TCR) repertoire within two Vb regions (Vβ8.3 and Vβ9). This can be partially explained by the H-2DbNPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2Db, including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the naïve and immune NPN3A-specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type (wt) virus, both are markedly lower than wt->wt challenge. Such decreased CD8+ responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Thus, the protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depend on peptide- MHC-I structural interactions and functional avidity. Our study does not support vaccine strategies that include immunization against commonly selected cross-reactive variants with mutations at partially-solvent exposed residues that have characteristics comparable to NPN3A. © 2010 Valkenburg et al. |
Persistent Identifier | http://hdl.handle.net/10722/241190 |
ISSN | 2023 Impact Factor: 5.5 2023 SCImago Journal Rankings: 2.223 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Valkenburg, Sophie A. | - |
dc.contributor.author | Gras, Stephanie | - |
dc.contributor.author | Guillonneau, Carole | - |
dc.contributor.author | La Gruta, Nicole L. | - |
dc.contributor.author | Thomas, Paul G. | - |
dc.contributor.author | Purcell, Anthony W. | - |
dc.contributor.author | Rossjohn, Jamie | - |
dc.contributor.author | Doherty, Peter C. | - |
dc.contributor.author | Turner, Stephen J. | - |
dc.contributor.author | Kedzierska, Katherine | - |
dc.date.accessioned | 2017-05-26T03:37:03Z | - |
dc.date.available | 2017-05-26T03:37:03Z | - |
dc.date.issued | 2010 | - |
dc.identifier.citation | PLoS Pathogens, 2010, v. 6, n. 8, p. 23-24 | - |
dc.identifier.issn | 1553-7366 | - |
dc.identifier.uri | http://hdl.handle.net/10722/241190 | - |
dc.description.abstract | Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. Pre- existing CD8+ T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP336-374 peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross-reactive T cell responses. The engineered virus induced a diminished CD8+ T cell response and selected a narrowed T cell receptor (TCR) repertoire within two Vb regions (Vβ8.3 and Vβ9). This can be partially explained by the H-2DbNPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2Db, including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the naïve and immune NPN3A-specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type (wt) virus, both are markedly lower than wt->wt challenge. Such decreased CD8+ responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Thus, the protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depend on peptide- MHC-I structural interactions and functional avidity. Our study does not support vaccine strategies that include immunization against commonly selected cross-reactive variants with mutations at partially-solvent exposed residues that have characteristics comparable to NPN3A. © 2010 Valkenburg et al. | - |
dc.language | eng | - |
dc.relation.ispartof | PLoS Pathogens | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | Protective efficacy of cross-reactive CD8<sup>+</sup> T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold | - |
dc.type | Article | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1371/journal.ppat.1001039 | - |
dc.identifier.pmid | 20711359 | - |
dc.identifier.scopus | eid_2-s2.0-77958146768 | - |
dc.identifier.volume | 6 | - |
dc.identifier.issue | 8 | - |
dc.identifier.spage | 23 | - |
dc.identifier.epage | 24 | - |
dc.identifier.eissn | 1553-7374 | - |
dc.identifier.isi | WOS:000281399900012 | - |
dc.identifier.issnl | 1553-7366 | - |