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Rühl, Geraldine; Niedl, Anna G.; Patronov, Atanas; Siewert, Katherina; Pinkert, Stefan; Kalemanov, Maria; Friese, Manuel A.; Attfield, Kathrine E.; Antes, Iris; Hohlfeld, Reinhard; Dornmair, Klaus (2016): Multiple sclerosis Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor. In: Neurology: Neuroimmunology & Neuroinflammation, Vol. 3, No. 4, e241
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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.