title: Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes.
abstract: The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid 'lock-and-key' binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an 'aromatic-cap' over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bulek
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.forename: Garry
authors.initials: G
authors.lastname: Dolton
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Florian
authors.initials: F
authors.lastname: Madura
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Robin R
authors.initials: RR
authors.lastname: Knight
authors.forename: Guo C
authors.initials: GC
authors.lastname: Huang
authors.forename: Nikolai
authors.initials: N
authors.lastname: Lissin
authors.forename: Peter E
authors.initials: PE
authors.lastname: Molloy
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology
chemical_list: D006649:Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell