Peptide length determines the outcome of TCR/peptide-MHCI engagement

Eukeruche-Makinde, Julia, Miles, John J., Van Den Berg, Hugo A., Skowera, Ania, Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396, Dolton, Garry Michael, Schauenburg, Andrea, Tan, Mai Ping, Pentier, Johanne, Llewellyn-Lacey, Sian, Miles, Kim M., Bulek, Anna, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Dockree, Tamsin, Trimby, Andrew R., Bailey, Mick, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Peakman, Mark, Burrows, Scott, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 and Wooldridge, Linda 2013. Peptide length determines the outcome of TCR/peptide-MHCI engagement. Blood -New York- 121 (7) , pp. 1112-1123. 10.1182/blood-2012-06-437202

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Abstract

αβ-TCRs expressed at the CD8+ T-cell surface interact with short peptide fragments (p) bound to MHC class I molecules (pMHCI). The TCR/pMHCI interaction is pivotal in all aspects of CD8+ T-cell immunity. However, the rules that govern the outcome of TCR/pMHCI engagement are not entirely understood, and this is a major barrier to understanding the requirements for both effective immunity and vaccination. In the present study, we discovered an unexpected feature of the TCR/pMHCI interaction by showing that any given TCR exhibits an explicit preference for a single MHCI-peptide length. Agonists of nonpreferred length were extremely rare, suboptimal, and often entirely distinct in sequence. Structural analysis indicated that alterations in peptide length have a major impact on antigenic complexity, to which individual TCRs are unable to adapt. This novel finding demonstrates that the outcome of TCR/pMHCI engagement is determined by peptide length in addition to the sequence identity of the MHCI-bound peptide. Accordingly, the effective recognition of pMHCI Ag, which is a prerequisite for successful CD8+ T-cell immunity and protective vaccination, can only be achieved by length-matched Ag-specific CD8+ T-cell clonotypes.

Item Type:	Article
Status:	Published
Schools:	Medicine
Publisher:	American Society of Hematology
ISSN:	0006-4971
Date of First Compliant Deposit:	1 September 2016
Last Modified:	27 Jul 2023 01:09
URI:	https://orca.cardiff.ac.uk/id/eprint/94128

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