Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease

The Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Immunity (Impact Factor: 21.56). 10/2012; 37(4):611-21. DOI: 10.1016/j.immuni.2012.07.013
Source: PubMed


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.

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    • "The crystal structures of class II HLA complexes with non-self-peptides derived from a plant have been determined for the HLA-DQ2·deamida- ted-gliadin [18], the HLA-DQ2.3·Gamma-gliadin [19], and the HLA-DQ8·deamidated-glutein [20] [21]. Nine specific amino acid residues in each peptide are accommodated in the peptide-binding groove, formed by the α and β chains. "
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    • "Finally, a very recent study shows biased TCR usage against HLA DQ8-restricted gliadin peptides in persons with celiac disease [53]. These new data show that TCR usage biased to TRBV9*01 underpins the recognition of HLA-DQ8-α-1-gliadin. "
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