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

Neurology Neuroimmunology Neuroinflammation. 2016 May 17. 3(4):e241. DOI: 10.1212/NXI.0000000000000241. eCollection 2016.

Authors/Editors: Rühl G, Niedl A, Parronov A, Siewert K, Pinkert S, Kalemanov M, Friese M A, Attfield K E, Antes I, Hohlfeld R, Dornmair K
Publication Date: 2016

2016_05_Rühl

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 CD81 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 CD81T-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 HLAA* 02:01.

 

 

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