title: Peptide length determines the outcome of TCR/peptide-MHCI engagement.
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.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Ekeruche-Makinde
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Hugo A
authors.initials: HA
authors.lastname: van den Berg
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.forename: Andrea J A
authors.initials: AJ
authors.lastname: Schauenburg
authors.forename: Mai Ping
authors.initials: MP
authors.lastname: Tan
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Pentier
authors.forename: Sian
authors.initials: S
authors.lastname: Llewellyn-Lacey
authors.forename: Kim M
authors.initials: KM
authors.lastname: Miles
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bulek
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.forename: Tamsin
authors.initials: T
authors.lastname: Williams
authors.forename: Andrew
authors.initials: A
authors.lastname: Trimby
authors.forename: Mick
authors.initials: M
authors.lastname: Bailey
authors.forename: Pierre
authors.initials: P
authors.lastname: Rizkallah
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002999:Clone Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D019151:Peptide Library; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*
chemical_list: D000941:Antigens; D015395:Histocompatibility Antigens Class I; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D016693:Receptors, Antigen, T-Cell, alpha-beta