Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease.
Celiac disease is a human leukocyte antigen (HLA)-DQ2- and/or DQ8-associated T cell-mediated disorder that is induced by dietary gluten. Although it is established how gluten peptides bind HLA-DQ8 and HLA-DQ2, it is unclear how such peptide-HLA complexes are engaged by the T cell receptor (TCR), a recognition event that triggers disease pathology. We show that biased TCR usage (TRBV9(∗)01) underpins the recognition of HLA-DQ8-α-I-gliadin. The structure of a prototypical TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-α-I-gliadin, in which all complementarity-determining region-β (CDRβ) loops interact with the gliadin peptide. Mutagenesis at the TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin interface provides an energetic basis for the Vβ bias. Moreover, CDR3 diversity accounts for TRBV9(∗)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.
The Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
Sophie E
SE
Broughton
Jan
J
Petersen
Alex
A
Theodossis
Stephen W
SW
Scally
Khai Lee
KL
Loh
Allan
A
Thompson
Jeroen
J
van Bergen
Yvonne
Y
Kooy-Winkelaar
Kate N
KN
Henderson
Travis
T
Beddoe
Jason A
JA
Tye-Din
Stuart I
SI
Mannering
Anthony W
AW
Purcell
James
J
McCluskey
Robert P
RP
Anderson
Frits
F
Koning
Hugh H
HH
Reid
Jamie
J
Rossjohn
D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005903:Gliadin / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D054730:Protein Interaction Domains and Motifs; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D005903:Gliadin