Determinants of gliadin-specific T cell selection in celiac disease

J Petersen, J van Bergen, KL Loh… - The Journal of …, 2015 - journals.aai.org
J Petersen, J van Bergen, KL Loh, Y Kooy-Winkelaar, DX Beringer, A Thompson, SF Bakker…
The Journal of Immunology, 2015journals.aai.org
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 …
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.
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