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CD8(+) T-cell cross-competition is governed by peptide-MHC class I stability

CD8(+) T-cell cross-competition is governed by peptide-MHC class I stability
CD8(+) T-cell cross-competition is governed by peptide-MHC class I stability
A major contributing factor to the final magnitude and breadth of CD8+ T-cell responses to complex antigens is immunodomination, where CD8+ T cells recognizing their cognate ligand inhibit the proliferation of other CD8+ T cells engaged with the same APC. In this study, we examined how the half-life of cell surface peptide–MHC class I complexes influences this phenomenon. We found that primary CD8+ T-cell responses to DNA vaccines in mice are shaped by competition among responding CD8+ T cells for nonspecific stimuli early after activation and prior to cell division. The susceptibility of CD8+ T cells to ‘domination’ was a direct correlate of higher kinetic stability of the competing CD8+ T-cell cognate ligand. When high affinity competitive CD8+ T cells were deleted by self-antigen expression, competition was abrogated. These findings show, for the first time to our knowledge, the existence of regulatory mechanisms that direct the responding CD8+ T-cell repertoire toward epitopes with high-stability interactions with MHC class I molecules. They also provide an insight into factors that facilitate CD8+ T-cell coexistence, with important implications for vaccine design and delivery.
cd8+ t cells, competition, immunodominance, mhc, peptide
0014-2980
256-263
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Stasakova, Jana
52cf3ca8-9c3d-4754-a32e-2bfe0519c27e
Dunscombe, Melanie S.
761f5609-1b0d-407f-b37e-0c64ef0fa54e
Ottensmeier, Christian H.
42b8a398-baac-4843-a3d6-056225675797
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Thirdborough, Stephen M.
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Stasakova, Jana
52cf3ca8-9c3d-4754-a32e-2bfe0519c27e
Dunscombe, Melanie S.
761f5609-1b0d-407f-b37e-0c64ef0fa54e
Ottensmeier, Christian H.
42b8a398-baac-4843-a3d6-056225675797
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Thirdborough, Stephen M.
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de

Galea, Ian, Stasakova, Jana, Dunscombe, Melanie S., Ottensmeier, Christian H., Elliott, Tim and Thirdborough, Stephen M. (2012) CD8(+) T-cell cross-competition is governed by peptide-MHC class I stability European Journal of Immunology, 42, (1), pp. 256-263. (doi:10.1002/eji.201142010). (PMID:22002320).

Record type: Article

Abstract

A major contributing factor to the final magnitude and breadth of CD8+ T-cell responses to complex antigens is immunodomination, where CD8+ T cells recognizing their cognate ligand inhibit the proliferation of other CD8+ T cells engaged with the same APC. In this study, we examined how the half-life of cell surface peptide–MHC class I complexes influences this phenomenon. We found that primary CD8+ T-cell responses to DNA vaccines in mice are shaped by competition among responding CD8+ T cells for nonspecific stimuli early after activation and prior to cell division. The susceptibility of CD8+ T cells to ‘domination’ was a direct correlate of higher kinetic stability of the competing CD8+ T-cell cognate ligand. When high affinity competitive CD8+ T cells were deleted by self-antigen expression, competition was abrogated. These findings show, for the first time to our knowledge, the existence of regulatory mechanisms that direct the responding CD8+ T-cell repertoire toward epitopes with high-stability interactions with MHC class I molecules. They also provide an insight into factors that facilitate CD8+ T-cell coexistence, with important implications for vaccine design and delivery.

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e-pub ahead of print date: 28 November 2011
Published date: January 2012
Keywords: cd8+ t cells, competition, immunodominance, mhc, peptide
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 204417
URI: http://eprints.soton.ac.uk/id/eprint/204417
ISSN: 0014-2980
PURE UUID: 7ded871c-2a7e-4f84-b04a-b89336d855b2
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102
ORCID for Tim Elliott: ORCID iD orcid.org/0000-0003-1097-0222

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Date deposited: 28 Nov 2011 14:43
Last modified: 18 Jul 2017 11:06

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Contributors

Author: Ian Galea ORCID iD
Author: Jana Stasakova
Author: Melanie S. Dunscombe
Author: Tim Elliott ORCID iD

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