Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor
Standard
Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor. / 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.
in: NEUROL-NEUROIMMUNOL, Jahrgang 3, Nr. 4, 17.05.2016, S. e241.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor
AU - Rühl, Geraldine
AU - Niedl, Anna G
AU - Patronov, Atanas
AU - Siewert, Katherina
AU - Pinkert, Stefan
AU - Kalemanov, Maria
AU - Friese, Manuel A
AU - Attfield, Kathrine E
AU - Antes, Iris
AU - Hohlfeld, Reinhard
AU - Dornmair, Klaus
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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.
AB - 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.
U2 - 10.1212/NXI.0000000000000241
DO - 10.1212/NXI.0000000000000241
M3 - SCORING: Journal article
C2 - 27231714
VL - 3
SP - e241
JO - NEUROL-NEUROIMMUNOL
JF - NEUROL-NEUROIMMUNOL
SN - 2332-7812
IS - 4
ER -