Ekeruche-Makinde, Julia, Miles, John J., van den Berg, Hugo A., Skowera, Ania, Cole, David K., Dolton, Garry, Schauenburg, Andrea J.A., Tan, Mai Ping, Pentier, Johanne M., Llewellyn-Lacey, Sian, Miles, Kim M., Bulek, Anna M., Clement, Mathew, Williams, Tamsin, Trimby, Andrew, Bailey, Mick, Rizkallah, Pierre, Rossjohn, Jamie, Peakman, Mark, Price, David A., Burrows, Scott R., Sewell, Andrew K., and Wooldridge, Linda (2013) Peptide length determines the outcome of TCR/peptide-MHCI engagement. Blood, 121 (7). pp. 1112-1123.

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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.

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