The length of the peptide in the MHC groove compartmentalizes the CD8+ T cell repertoire (P1186)

Abstract

Abstract TCRs expressed at the CD8+ T-cell surface interact with short peptide fragments 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. Using large combinatorial peptide arrays, each containing between twenty billion to forty quadtrillion distinct peptides, we have discovered an unexpected feature of the TCR/pMHCI interaction by showing that all TCRs exhibit an explicit preference for an MHCI-bound peptide of defined 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 surprising finding, that the CD8+ T cell repertoire is rigorously "compartmentalized" by peptide length, has important consequences for cellular immune system research and vaccine development.