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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Available from: Stuart I Mannering, Jul 09, 2014
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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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    ABSTRACT: The major allergen, Cry j 1, was isolated from Japanese cedar Cryptomeria japonica (Cry j) pollen and was shown to react with immunoglobulin E antibodies in the sera from pollinosis patients. We previously reported that the frequency of HLA-DP5 was significantly higher in pollinosis patients and the immunodominant peptides from Cry j 1 bound to HLA-DP5 to activate Th2 cells. In the present study, we determined the crystal structure of the HLA-DP5 heterodimer in complex with a Cry j 1-derived nine-residue peptide, at 2.4 Å resolution. The peptide-binding groove recognizes the minimal peptide with 10 hydrogen bonds, including those between the negatively charged P1 pocket and the Lys side chain at the first position in the peptide sequence. We confirmed that HLA-DP5 exhibits the same Cry j 1-binding mode in solution, through pull-down experiments using structure-based mutations of Cry j 1. We also identified the characteristic residues of HLA-DP5 that are responsible for the distinct properties of the groove, by comparing the structure of HLA-DP5 and the previously reported structures of HLA-DP2 in complexes with pDRA of the self-antigen. The comparison revealed that the HLA-DP5·pCry j 1 complex forms several hydrogen bond/salt bridge networks between the receptor and the antigen that were not observed in the HLA-DP2·pDRA complex. Evolutionary considerations have led us to conclude that HLA-DP5 and HLA-DP2 represent two major groups of the HLA-DP family, in which the properties of the P1 and P4 pockets have evolved and acquired the present ranges of epitope peptide-binding specificities.
    Journal of Molecular Biology 08/2014; 426(17). DOI:10.1016/j.jmb.2014.06.020 · 4.33 Impact Factor
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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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    ABSTRACT: Type 1 diabetes (T1D) is a T cell-mediated disease. It is strongly associated with susceptibility haplotypes within the major histocompatibility complex, but this association accounts for an estimated 50% of susceptibility. Other studies have identified as many as 50 additional susceptibility loci, but the effect of most is very modest (odds ratio (OR) <1.5). What accounts for the "missing heritability" is unknown and is often attributed to environmental factors. Here we review new data on the cognate ligand of MHC molecules, the T cell receptor (TCR). In rats, we found that one allele of a TCR variable gene, V β 13A, is strongly associated with T1D (OR >5) and that deletion of V β 13+ T cells prevents diabetes. A role for the TCR is also suspected in NOD mice, but TCR regions have not been associated with human T1D. To investigate this disparity, we tested the hypothesis in silico that previous studies of human T1D genetics were underpowered to detect MHC-contingent TCR susceptibility. We show that stratifying by MHC markedly increases statistical power to detect potential TCR susceptibility alleles. We suggest that the TCR regions are viable candidates for T1D susceptibility genes, could account for "missing heritability," and could be targets for prevention.
    Journal of Diabetes Research 03/2013; 2013:737485. DOI:10.1155/2013/737485 · 2.16 Impact Factor
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    ABSTRACT: Autoreactive CD4+ T cells initiate the chronic autoimmune disease Type-1 diabetes (T1D), in which multiple environmental and genetic factors are involved. The association of HLA, especially the DR-DQ loci, with risk for T1D is well documented. However, the molecular mechanisms are poorly understood. In this review, we explore the structural characteristics of HLA-DQ and the role of HLA-DM function as they may contribute to an understanding of autoreactive T cell development in T1D.
    Frontiers in Immunology 08/2013; 4:262. DOI:10.3389/fimmu.2013.00262
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