Determinants of Gliadin-Specific T Cell Selection in Celiac Disease

In HLA-DQ8 –associated celiac disease (CD), the pathogenic T cell response is directed toward an immunodominant α-gliadin–derived peptide (DQ8-glia-α1). However, our knowledge of TCR gene usage within the primary intestinal tissue of HLA-DQ8 + CD patients is limited. We identified two populations of HLA-DQ8-glia-α1 tetramer + CD4 + T cells that were essentially undetectable in biopsy samples from patients on a gluten-free diet but expanded rapidly and specifically after antigenic stimulation. Distinguished by expression of TRBV9, both T cell populations displayed biased clonotypic repertoires and reacted similarly against HLA-DQ8-glia-α1. In particular, TRBV9 paired most often with TRAV26-2, whereas the majority of TRBV9 − TCRs used TRBV6-1 with no clear TRAV gene preference. Strikingly, both tetramer + /TRBV9 + and tetramer + /TRBV9 − T cells possessed a non–germline-encoded arginine residue in their CDR3α and CDR3β loops, respectively. Comparison of the crystal structures of three TRBV9 + TCRs and a TRBV9 − TCR revealed that, as a result of distinct TCR docking modes, the HLA-DQ8-glia-α1 contacts mediated by the CDR3-encoded arginine were almost identical between TRBV9 + and TRBV9 − TCRs. In all cases, this interaction centered on two hydrogen bonds with a specific serine residue in the bound peptide. Replacement of serine with alanine at this position abrogated TRBV9 + and TRBV9 − clonal T cell proliferation in response to HLA-DQ8-glia-α1. Gluten-specific memory CD4 + T cells with structurally and functionally conserved TCRs therefore predominate in the disease-affected tissue of patients with HLA-DQ8–mediated CD.