T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease.
Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-α1a and DQ2.5-glia-α2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-α2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3β loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-α1a and DQ2.5-glia-α2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
1] Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. [2].
Jan
J
Petersen
1] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. [2].
Veronica
V
Montserrat
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Jorge R
JR
Mujico
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
Khai Lee
KL
Loh
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
Dennis X
DX
Beringer
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Menno
M
van Lummel
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Allan
A
Thompson
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
M Luisa
ML
Mearin
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
Joachim
J
Schweizer
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Yvonne
Y
Kooy-Winkelaar
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Jeroen
J
van Bergen
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Jan W
JW
Drijfhout
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
Wan-Ting
WT
Kan
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
Nicole L
NL
La Gruta
ImmusanT, Inc., Cambridge, Massachusetts, USA.
Robert P
RP
Anderson
1] Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. [2] [3].
Hugh H
HH
Reid
1] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. [2] [3].
Frits
F
Koning
1] Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. [2] Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK. [3] Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. [4] [5].
Jamie
J
Rossjohn
D002446:Celiac Disease / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D005903:Gliadin / Q000737:chemistry* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000737:chemistry*; D006801:Humans; D055261:Immunogenetic Phenomena; D008958:Models, Molecular; D008968:Molecular Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*; D014908:Triticum
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D011948:Receptors, Antigen, T-Cell; D005903:Gliadin