title: Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity.
abstract: The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide-major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I-restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key-like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bulek
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Schauenberg
authors.forename: Barbara
authors.initials: B
authors.lastname: Szomolay
authors.forename: William
authors.initials: W
authors.lastname: Rittase
authors.forename: Andrew
authors.initials: A
authors.lastname: Trimby
authors.forename: Prithiviraj
authors.initials: P
authors.lastname: Jothikumar
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D000595:Amino Acid Sequence; D015551:Autoimmunity; D002999:Clone Cells; D003429:Cross Reactions; D015234:HLA-A Antigens / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015234:HLA-A Antigens; D007328:Insulin; D008024:Ligands; D009842:Oligopeptides; D011498:Protein Precursors; D011948:Receptors, Antigen, T-Cell; C013737:preproinsulin