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

The alphabeta T-cell receptors (TCRs) expressed at the CD8(+) T-cell surface interact with short peptide fragments (p), bound to major histocompatibility complex class I (MHCI) molecules. 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 which is a major barrier to understanding the requirements for both effective immunity and vaccination. Here, we have 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 non-preferred 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 antigen, which is a prerequisite for successful CD8(+) T-cell immunity and protective vaccination, can only be achieved by length-matched antigen-specific CD8(+) T-cell clonotypes.