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

Abstract

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.

A Novel Approach to Tracking Antigen-Experienced CD4 T Cells into Functional Compartments via Tandem Deep and Shallow TCR Clonotyping

“…The fact that these clonotypes are not found in all subjects as Ag responsive could be attributable to several factors, including sampling biases (38) and pairing with TCRVa-chains nonpermissive for the specific pHLA complex. Our findings are in keeping with recent in-depth studies of gluten epitope-specific CD4 T cells, which, despite being focused by repeated exposure to the same exogenous antigenic peptides presented by HLA-DQ8 and bearing high-affinity TCRs, show TRBV9*01 bias but very little conservation of residues in the CDR3b region (39). The intense privacy of Ag-specific responses that we observed indicates that the development of clonotypic tracking for biomarker purposes may need to be subject specific.…”

Determinants of Gliadin-Specific T Cell Selection in Celiac Disease

“…Written informed consent was obtained from each subject before enrollment. Patients S, T, vL, LS, and SP have been described previously (9,15). Additional HLA class II genotypes were as follows: patient E, HLA-DQA1*0301-DQB1*0302 homozygous; patient B, HLA-DQA1*0301-DQB1*0302 homozygous; patient Bel, HLA-DQA1*03/03-DQB1*0301/ 0302 heterozygous; patient C, HLA-DQA1*0101/0301-DQB1*0501/0302 heterozygous.…”

“…Such observations generally reflect structural and/ or recombinatorial constraints (13,14). Indeed, the first insights into the molecular basis for this biased TRBV usage have been obtained via crystallographic studies (9,10).…”

“…In particular, T cells specific for the DQ2.5-glia-a2 peptide preferentially express TRBV7-2, whereas those specific for DQ8-glia-a1 typically use TRBV9 (9)(10)(11)(12). Such observations generally reflect structural and/ or recombinatorial constraints (13,14).…”

“…A single crystal structure of a TRBV9 + TCR-HLA-DQ8-glia-a1 complex shows that two amino acid residues virtually unique to TRBV9 are essential for TCR binding to the HLA-DQ8-glia-a1 complex, thereby providing a potential explanation for TRBV9 bias in HLA-DQ8-mediated CD (9). However, the observed bias toward TRBV9 does not necessarily extend to the affected intestinal tissue of patients because the HLA-DQ8-restricted T cells examined in this study were derived from long-term biopsy cultures.…”