title: Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor.
abstract: OBJECTIVE
  To identify target antigens presented by human leukocyte antigen (HLA)-A*02:01 to the myelin-reactive human T-cell receptor (TCR) 2D1, which was originally isolated from a CD8+ T-cell clone recognizing proteolipid protein (PLP) in the context of HLA-A*03:01, we employed a new antigen search technology.
  
  
  METHODS
  We used our recently developed antigen search technology that employs plasmid-encoded combinatorial peptide libraries and a highly sensitive single cell detection system to identify endogenous candidate peptides of mice and human origin. We validated candidate antigens by independent T-cell assays using synthetic peptides and refolded HLA:peptide complexes. A molecular model of HLA-A*02:01:peptide complexes was obtained by molecular dynamics simulations.
  
  
  RESULTS
  We identified one peptide from glycerolphosphatidylcholine phosphodiesterase 1, which is identical in mice and humans and originates from a protein that is expressed in many cell types. When bound to HLA-A*02:01, this peptide cross-stimulates the PLP-reactive HLA-A3-restricted TCR 2D1. Investigation of molecular details revealed that the peptide length plays a crucial role in its capacity to bind HLA-A*02:01 and to activate TCR 2D1. Molecular modeling illustrated the 3D structures of activating HLA:peptide complexes.
  
  
  CONCLUSIONS
  Our results show that our antigen search technology allows us to identify new candidate antigens of a presumably pathogenic, autoreactive, human CD8+ T-cell-derived TCR. They further illustrate how this TCR, which recognizes a myelin peptide bound to HLA-A*03:01, may cross-react with an unrelated peptide presented by the protective HLA class I allele HLA-A*02:01.
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rühl
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Niedl
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Atanas
authors.initials: A
authors.lastname: Patronov
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Katherina
authors.initials: K
authors.lastname: Siewert
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pinkert
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kalemanov
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Kathrine E
authors.initials: KE
authors.lastname: Attfield
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Antes
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.affiliation: Institute of Clinical Neuroimmunology (G.R., A.G.N., K.S., R.H., K.D.) and Munich Cluster for Systems Neurology (SyNergy) (R.H., K.D.), Ludwig-Maximilian-University, Munich; Department of Life Sciences (A.P., M.K., I.A.), Technical University Munich, Freising; Max Planck Institute of Biochemistry (S.P.), Martinsried; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany; MRC Human Immunology Unit (K.E.A.), Radcliffe Department of Medicine, Weatherall, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK; and Center for Integrated Protein Science Munich (CIPSM) (I.A.), Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Dornmair