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

J Ekeruche-Makinde, JJ Miles… - Blood, The Journal …, 2013 - ashpublications.org
J Ekeruche-Makinde, JJ Miles, HA Van Den Berg, A Skowera, DK Cole, G Dolton…
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
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 …
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.
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