title: Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase.
abstract: T-cell cross-reactivity is essential for effective immune surveillance but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focused antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase. The ILA1 TCR contacted its pMHC with a broad peptide binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding, the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts apparent in the structure correlated well with the level of degeneracy at different peptide positions. Thus, the ILA1 TCR was less tolerant of changes at peptide residues that were at, or adjacent to, key contact sites. This study provides new insights into the molecular mechanisms that control T-cell cross-reactivity with important implications for pathogen surveillance, autoimmunity, and transplant rejection.
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom, coledk@cf.ac.uk.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.affiliation: the Mathematics Institute, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: van den Berg
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Angharad
authors.initials: A
authors.lastname: Lloyd
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Crowther
authors.affiliation: the Cardiff University School of Dentistry, Heath Park, Cardiff CF14 4XY, United Kingdom.
authors.forename: Konrad
authors.initials: K
authors.lastname: Beck
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Ekeruche-Makinde
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.|the Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.|James Cook University, Cairns, Queensland 4870, Australia, and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bulek
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Schauenburg
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Aaron
authors.initials: A
authors.lastname: Wall
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Bruno
authors.initials: B
authors.lastname: Laugel
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.affiliation: the Faculty of Health Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.affiliation: From the Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom, sewellak@cf.ac.uk.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D019098:Telomerase / Q000737:chemistry / Q000276:immunology
chemical_list: D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C509186:TERT protein, human; D019098:Telomerase
keywords: T cell degeneracy; T cell receptor; T cells; X-ray crystallography; peptides; surface plasmon resonance (SPR); telomerase; tumor immunology