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  Multiple sclerosis Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor

Ruehl, G., Niedl, A. G., Patronov, A., Siewert, K., Pinkert, S., Kalemanov, M., et al. (2016). Multiple sclerosis Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor. Neurology: Neuroimmunology & Neuroinflammation, 3(4): e241. doi:10.1212/NXI.0000000000000241.

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Neurol Neuroimmunol Neuroinflamm-2016-Rühl-.pdf (Verlagsversion), 714KB
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 Urheber:
Ruehl, Geraldine1, Autor
Niedl, Anna G.1, Autor
Patronov, Atanas1, Autor
Siewert, Katherina1, Autor
Pinkert, Stefan2, Autor           
Kalemanov, Maria1, Autor
Friese, Manuel A.1, Autor
Attfield, Kathrine E.1, Autor
Antes, Iris1, Autor
Hohlfeld, Reinhard1, Autor
Dornmair, Klaus1, Autor
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1external, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Schlagwörter: PROTEOLIPID PROTEIN; CROSS-REACTIVITY; STRUCTURAL BASIS; PEPTIDE; RECOGNITION; TCR; IDENTIFICATION; EXPRESSION; LIBRARIES; SELECTIONNeurosciences & Neurology;
 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2016-05-17
 Publikationsstatus: Online veröffentlicht
 Seiten: 10
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: ISI: 000391168900007
DOI: 10.1212/NXI.0000000000000241
 Art des Abschluß: -

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Titel: Neurology: Neuroimmunology & Neuroinflammation
Genre der Quelle: Zeitschrift
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Affiliations:
Ort, Verlag, Ausgabe: American Academy of Neurology
Seiten: - Band / Heft: 3 (4) Artikelnummer: e241 Start- / Endseite: - Identifikator: ISSN: 2332-7812